EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, SEPTEMBER 22, 2015

Media Advisory: To contact Anthony V. D’Amico, M.D., Ph.D., call Lori Schroth at 617-525-6374 or email ljschroth@partners.org.

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Among men with unfavorable-risk prostate cancer and moderate or severe co-existing illness, long-term follow-up finds that radiation therapy alone vs radiation therapy and androgen deprivation therapy was associated with decreased overall and cardiac mortality, according to a study in the September 22/29 issue of JAMA.

Six months of androgen deprivation therapy (ADT) and radiation therapy (RT) vs RT alone prolongs survival and is the standard treatment for unfavorable-risk prostate cancer. A post-randomization analysis suggested that men with moderate or severe comorbidity (co-existing illness) had no survival benefit from combined therapy. Using updated data from this trial, Anthony V. D’Amico, M.D., Ph.D., of Brigham and Women’s Hospital, Boston, and colleagues compared overall survival and mortality from prostate cancer, cardiac, or other causes in all men and those within comorbidity subgroups by treatment group. Between December 1995 and April 2001, 206 men with unfavorable-risk prostate cancer were randomly assigned to receive RT alone or RT and 6 months of ADT at 3 academic and 3 community-based centers in Massachusetts.

The researchers found that at a median follow-up of 17 years, RT alone vs RT and ADT was associated with significantly decreased overall and cardiac mortality in men with moderate or severe comorbidity. This is in contrast to no association with overall mortality at a median follow-up of 8 years. Although RT alone vs RT and ADT was associated with increased mortality in men with none or minimal comorbidity, mortality among all men assigned to RT alone was not significantly increased.

“The association of treatment with RT alone with decreased cardiac and overall mortality in men with moderate or severe comorbidity suggests that administering ADT to treat unfavorable-risk prostate cancer in these men should be carefully considered,” the authors write.

(doi:10.1001/jama.2015.8577; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, SEPTEMBER 15, 2015

Media Advisory: To contact Mingguang He, M.D., Ph.D., email mingguang_he@yahoo.com. To contact editorial author Michael X. Repka, M.D., M.B.A., call Marin Hedin at 410-502-9429 or email mhedin2@jhmi.edu.

To place an electronic embedded link to this study and editorial in your story This link to the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.10803 This will be the link to the editorial: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.10723

The addition of a daily outdoor activity class at school for three years for children in Guangzhou, China, resulted in a reduction in the rate of myopia (nearsightedness, the ability to see close objects more clearly than distant objects), according to a study in the September 15 issue of JAMA.

Myopia has reached epidemic levels in young adults in some urban areas of East and Southeast Asia. In these areas, 80 percent to 90 percent of high school graduates now have myopia. Myopia also appears to be increasing, more slowly, in populations of European and Middle Eastern origin. Currently, there is no effective intervention for preventing onset. Recent studies have suggested that time spent outdoors may prevent the development of myopia, according to background information in the article.

Mingguang He, M.D., Ph.D., of Sun Yat-sen University, Guangzhou, China, and colleagues conducted a study in which children in grade 1 from 12 primary schools in Guangzhou, China (six intervention schools [n = 952 students]; six control schools [n = 951 students], were assigned to 1 additional 40-minute class of outdoor activities, added to each school day, and parents were encouraged to engage their children in outdoor activities after school hours, especially during weekends and holidays (intervention schools); or children and parents continued their usual pattern of activity (control schools). The average age of the children was 6.6 years.

The 3-year cumulative incidence rate of myopia was 30.4 percent (259 cases among 853 eligible participants) in the intervention group and 39.5 percent (287 cases among 726 eligible participants) in the control group. Cumulative change in spherical equivalent refraction (myopic shift) after 3 years was significantly less in the intervention group than in the control group.

“Our study achieved an absolute difference of 9.1 percent in the incidence rate of myopia, representing a 23 percent relative reduction in incident myopia after 3 years, which was less than the anticipated reduction. However, this is clinically important because small children who develop myopia early are most likely to progress to high myopia, which increases the risk of pathological myopia. Thus a delay in the onset of myopia in young children, who tend to have a higher rate of progression, could provide disproportionate long-term eye health benefits,” the authors write.

“Further studies are needed to assess long-term follow-up of these children and the generalizability of these findings.”

(doi:10.1001/jama.2015.10803; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Editorial: Prevention of Myopia in Children

Michael X. Repka, M.D., M.B.A., of the Johns Hopkins University School of Medicine, Baltimore, comments on the findings of this study in an accompanying editorial.

“Future studies should include information about the content of the additional outdoor activity, if the activity could be standardized, and how it differs from other studies. This information could guide further study and implementation of outdoor activities in the school setting. Establishing the long-term effect of additional outdoor activities on the development and progression of myopia is particularly important because the intervention is essentially free and may have other health benefits.”

“Given the popular appeal of increased outdoor activities to improve the health of school-aged children in general, the potential benefit of slowing myopia development and progression by those same activities is difficult to ignore. Although prescribing this approach with the intent of helping to prevent myopia would appear to have no risk, parents should understand that the magnitude of the effect is likely to be small and the durability is uncertain.”

(doi:10.1001/jama.2015.10723; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, SEPTEMBER 15, 2015

Media Advisory: To contact Anupam B. Jena, M.D., Ph.D., call David Cameron at 617-432-0441 or email David_Cameron@hms.harvard.edu. To contact Robert Sege, M.D., Ph.D., call David Ball at 617-243-9950 or email david@ballcg.com. To contact editorial co-author Carrie L. Byington, M.D., call Julie Kiefer at 801-587-1293 or email julie.kiefer@utah.edu.

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Women are less likely than men to be full professors at U.S. medical schools, and receive less start-up support from their institutions for biomedical research, according to two studies in the September 15 issue of JAMA.

Women now make up half of all U.S. medical school graduates. However, sex disparities in senior faculty rank persist in academic medicine. Whether differences in age, experience, specialty, and research productivity between sexes explain persistent disparities in faculty rank has not been studied. Anupam B. Jena, M.D., Ph.D., of Harvard Medical School, Boston, and colleagues analyzed sex differences in faculty rank using a comprehensive database of U.S. physicians with medical school faculty appointments in 2014 (91,073 physicians; 9.1 percent of all U.S. physicians), linked to information on physician sex, age, years since residency, specialty, publications, National Institutes of Health (NIH) funding, and clinical trial investigation.

In all, there were 30,464 women who were medical faculty vs 60,609 men. Of those, 11.9 percent of women vs 28.6 percent of men had full-professor appointments. Women faculty were younger and disproportionately represented in internal medicine and pediatrics. The average total number of publications for women was 11.6 vs 24.8 for men; the average first- or last-author publications for women was 5.9 vs 13.7 for men.

Among 9.1 percent of medical faculty with an NIH grant, 6.8 percent were women and 10.3 percent were men. In all, 6.4 percent of women vs 8.8 percent of men had a trial registered on ClinicalTrials.gov. After adjustment for age, years since residency, specialty, and measures of research productivity, men were still significantly more likely than women to have achieved full-professor status. Sex differences in full professorship were present across nearly all specialties and were consistent across medical schools with highly and less highly ranked research programs.

The researchers also found that women were less likely than men to hold the rank of associate or full professor (a combined outcome) than to hold the rank of assistant professor and that women were less likely to hold the rank of full professor than hold the rank of associate professor.

The authors write that women may face difficulties finding effective mentors and receiving recognition from senior colleagues, workplace discrimination, and inequitable allocation of institutional resources. “These challenges may adversely affect research productivity and may also explain why even after adjusting for research productivity, women are still less likely than men to be full professors.”

(doi:10.1001/jama.2015.10803; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: The authors report a funding grant from the Office of the Director, National Institutes of Health. All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

In another study, Robert Sege, M.D., Ph.D., of Health Resources in Action, Boston, and colleagues examined sex differences in institutional support for junior biomedical researchers.

Women are underrepresented in the biomedical research workforce. Only 30 percent of funded investigators are women. Junior faculty women have fewer peer-reviewed publications than men and are more often on clinician-educator (vs traditional research) tracks. One reason may be differences in early-career institutional support, according to background information in the article.

Application data from two New England biomedical research programs administered by the Medical Foundation Division of Health Resources in Action were analyzed. Data on start-up support provided by the employing institution (i.e., salary and other support, including research technicians, equipment, and supplies) from all applications during 2012-2014 were extracted. The researchers compared support for men and women overall, and by scientific focus and terminal degree.

The study included 219 applicants (127 men and 92 women). Most applicants (67 percent) held Ph.D. degrees. Women were in clinical research more frequently than men. There were no differences between men and women in terminal degree or years since receiving terminal degree. Overall, men reported significantly higher start-up support (median, $889,000) than women (median, $350,000); 51 men (40 percent) and 11 women (12 percent) reported support of more than $1 million.

Men had higher support regardless of degree, but the difference was statistically significant only for persons with Ph.D. degrees. In basic sciences, men reported significantly more start-up support than women. Experience (years since receiving terminal degree) did not correlate with start-up package size for men, women, or overall.

“In this preliminary study of early-career grant applicants administered by 1 organization, junior faculty women received significantly less start-up support from their institutions than men,” the authors write. “This first look suggests the need for systematic study of sex differences in institutional support and the relationship to career trajectories.”

(doi:10.1001/jama.2015.8517; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: The Medical Foundation Division of Health Resources in Action provided access to the administrative data. The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Editorial: Addressing Disparities in Academic Medicine

“These 2 articles add to the abundance of literature focusing on the disparities of careers of women in academic medicine. Importantly, similar disparities exist for individuals from racial and ethnic minorities and for those from other marginalized communities,” write Carrie L. Byington, M.D., and Vivian Lee, M.D., Ph.D., M.B.A., of the University of Utah, Salt Lake City, in an accompanying editorial.

“As the training ground for future generations of health care providers and biomedical scientists, academic medical centers should ensure that their students, faculty, and staff represent the people they serve and that all can contribute to their fullest potential. It is time for academic medicine to move forward.”

(doi:10.1001/jama.2015.10664; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, SEPTEMBER 15, 2015

Media Advisory: To contact Yannick Le Manach, M.D., Ph.D., call Susan Emigh at 905-525-9140, ext. 22555 or email emighs@mcmaster.ca.

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Patients undergoing surgery for a hip fracture were older and had more medical conditions than patients who underwent an elective total hip replacement, factors that may contribute to the higher risk of in-hospital death and major postoperative complications experienced by hip fracture surgery patients, according to a study in the September 15 issue of JAMA.

Although hip surgery can improve mobility and pain, it can be associated with major postoperative medical complications and mortality. Patients undergoing surgery for a hip fracture are at substantially higher risk of mortality and medical complications compared with patients undergoing an elective total hip replacement (THR). The effect of older age and other medical conditions associated with hip fracture on this increased risk has not been known, according to background information in the article.

Yannick Le Manach, M.D., Ph.D., of McMaster University, Hamilton, Ontario, Canada and colleagues examined if there was a difference in hospital mortality among patients who underwent hip fracture surgery relative to an elective THR, after adjustment for age, sex, and preoperative medical conditions. Using the French National Hospital Discharge Database, the researchers included patients older than 45 years who underwent hip surgery at French hospitals from January 2010 to December 2013. The International Statistical Classification of Diseases and Related Health Problems, 10th Revision, codes were used to determine patients’ co-existing conditions and complications after surgery.

A total of 690,995 eligible patients were included from 864 centers in France. Patients undergoing elective THR surgery (n = 371,191) were younger, more commonly men, and had less medical comorbidity compared with patients undergoing hip fracture surgery. Following hip fracture surgery (n = 319,804), 10,931 patients (3.4 percent) died before hospital discharge and 669 patients (0.18 percent) died after elective THR.

Analysis of the matched populations (n = 234,314) demonstrated a higher risk of mortality (1.8 percent for hip fracture surgery vs 0.3 percent for elective THR) and of major postoperative complications (5.9 percent for hip fracture surgery vs 2.3 percent for elective THR) among patients undergoing hip fracture surgery.

“Patients undergoing surgery for a hip fracture were older and had more comorbidities than patients who underwent an elective THR, and these differences accounted for some of the difference in outcomes between these groups,” the authors write.

“If the absolute risk increases of 1.51 percent for in-hospital mortality and 3.54 percent for major postoperative complications were modifiable, they would be consistent with the number needed to treat of 59 patients for in-hospital mortality and 28 patients for major postoperative complications. Hip fracture may be associated with physiologic processes that are not present in circumstances leading to elective THR and increase the risk of morbidity and mortality following surgery.”

“Further studies are needed to define the causes for these differences.”

(doi:10.1001/jama.2015.10842; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, SEPTEMBER 8, 2015

Media Advisory: To contact Andy Menke, Ph.D., call Mona Feldman at 301-628-3000 or email MFeldman@s-3.com. To contact editorial co-author William H. Herman, M.D., M.P.H., call Kylie O’Brien at 734-764-2220 or email kylieo@med.umich.edu.

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In 2011-2012, the estimated prevalence of diabetes among U.S. adults was 12 percent to 14 percent and the prevalence of prediabetes was 37 percent to 38 percent, indicating that about half of the U.S. adult population has either diabetes or prediabetes, according to a study in the September 8 issue of JAMA. Though data from recent years suggests that the increasing prevalence of diabetes may be leveling off.

Diabetes is a major cause of illness and death in the United States, costing an estimated $245 billion in 2012 due to increased use of health resources and lost productivity. Andy Menke, Ph.D., of Social & Scientific Systems Inc., Silver Spring, Md., and colleagues estimated the U.S. prevalence and trends in diabetes and undiagnosed diabetes using National Health and Nutrition Examination Survey (NHANES) data. The researchers included data from surveys conducted between 1988-1994 and 1999-2012; 2,781 adults from 2011-2012 were used to estimate recent prevalence and an additional 23,634 adults from 1988-2010 were used to estimate trends.

The prevalence of diabetes was defined using a previous diagnosis of diabetes or, if diabetes was not previously diagnosed, by (1) a hemoglobin A_1c level of 6.5 percent or greater or a fasting plasma glucose (FPG) level of 126 mg/dL or greater (hemoglobin A_1c or FPG definition) or (2) additionally including 2-hour plasma glucose (2-hour PG) level of 200 mg/dL or greater (hemoglobin A_1c, FPG, or 2-hour PG definition). Prediabetes was defined with certain levels of these markers.

Among the findings:

In the overall 2011-2012 population, the unadjusted prevalence (using the hemoglobin A_1c, FPG, or 2-hour PG definitions for diabetes and prediabetes) was 14.3 percent for total diabetes, 9.1 percent for diagnosed diabetes, 5.2 percent for undiagnosed diabetes, and 38 percent for prediabetes; among those with diabetes, 36.4 percent were undiagnosed.

Compared with non-Hispanic white participants (11.3 percent), the prevalence of total diabetes (using the hemoglobin A_1c, FPG, or 2-hour PG definition) was higher among non-Hispanic black participants (21.8 percent), non-Hispanic Asian participants (20.6 percent), and Hispanic participants (22.6 percent).

The prevalence of prediabetes was greater than 30 percent in all sex and racial/ethnic categories, and generally highest among non-Hispanic white individuals and non-Hispanic black individuals.

The percentage of cases that were undiagnosed was higher among non-Hispanic Asian participants (50.9 percent) and Hispanic participants (49 percent) than all other racial/ethnic groups.

The prevalence of total diabetes (using the hemoglobin A_1c or FPG definition) increased from 9.8 percent) in 1988-1994 to 10.8 percent in 2001-2002 to 12.4 percent in 2011-2012 and increased significantly in every age group, in both sexes, in every racial/ethnic group and by all education levels.

The authors note that although there was an increase in diabetes prevalence between 1988- 1994 and 2011-2012, prevalence estimates changed little between 2007-2008 and 2011-2012. “This plateauing of diabetes prevalence is consistent with obesity trends in the United States showing a leveling off around the same period.”

(doi:10.1001/jama.2015.10029; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: This work was supported by a contract from the National Institute of Diabetes and Digestive and Kidney Diseases. The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Editorial: Prevalence of Diabetes in the United States

“Although obesity and type 2 diabetes remain major clinical and public health problems in the United States, the current data provide a glimmer of hope,” write William H. Herman, M.D., M.P.H., and Amy E. Rothberg, M.D., Ph.D., of the University of Michigan Health System, Ann Arbor, in an accompanying editorial.

“The shift in cultural attitudes toward obesity, the American Medical Association’s (AMA’s) recognition of obesity as a disease, and the increasing focus on societal interventions to address food policy and the built environment are beginning to address some of the broad environmental forces that have contributed to the epidemic of obesity. The effort of the AMA to promote screening, testing, and referral of high-risk patients for diabetes prevention through its Prevent Diabetes STAT program and the CDC’s efforts to increase the availability of diabetes prevention programs, ensure their quality, and promote their use appear to be helping to identify at-risk individuals and provide the infrastructure to support individual behavioral change.”

“Providing insurance coverage for intensive behavioral therapies for obesity and using behavioral economic approaches to encourage their uptake are further removing barriers to patient engagement and are providing strong incentives for individual behavioral change. Together, these multifaceted approaches addressing both environmental factors and individual behaviors appear to be slowing the increase in obesity and diabetes, and facilitating the diagnosis and management of diabetes. Progress has been made, but expanded and sustained efforts will be required.”

(doi:10.1001/jama.2015.10030; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Herman reported receiving personal fees and other from Merck Sharp & Dahme and Lexicon Pharmaceuticals; and personal fees from Profil Institute for Clinical Research. No other disclosures were reported.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, SEPTEMBER 8, 2015

Media Advisory: To contact Barbara J. Stoll, M.D., call Holly Korschun at 404-727-3990 or email hkorsch@emory.edu. To contact editorial author Roger F. Soll, M.D., call Jennifer Nachbur at 802-656-7875 or email jennifer.nachbur@uvm.edu.

To place an electronic embedded link to this study and editorial in your story This link to the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.10244 This will be the link to the editorial: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.10911

 Over the last 20 years, complications have decreased and survival has improved for extremely preterm infants, according to a study in the September 8 issue of JAMA.

Advances in medicine over the past 2 decades have changed care for mothers in preterm labor and for extremely preterm infants. Evaluation of current in-hospital complications and mortality data among extremely preterm infants is important in counseling families and considering new interventions to improve outcomes. Barbara J. Stoll, M.D., of the Emory University School of Medicine, Atlanta, and colleagues reviewed trends in maternal/neonatal care, complications, and mortality among 34,636 infants, 22 to 28 weeks’ gestation, birth weight of 14.1 ounces to 3.3 lbs. born at 26 Neonatal Research Network centers between 1993 and 2012.

The researchers found that survival increased between 2009 and 2012 for infants at 23 weeks’ gestation (27 percent to 33 percent) and 24 weeks (63 percent to 65 percent), with smaller relative increases for infants at 25 and 27 weeks’ gestation, and no change for infants at 22, 26, and 28 weeks’ gestation. Survival without major complications increased approximately 2 percent per year for infants at 25 to 28 weeks’ gestation, with no change for infants at 22 to 24 weeks’ gestation.

“Perhaps the most important new finding is a significant increase in survival without major neonatal morbidity [complication] for infants born at 25 through 28 weeks. Although overall survival increased for infants aged 23 and 24 weeks, few infants younger than 25 weeks’ gestational age survived without major neonatal morbidity, underscoring the continued need for interventions to improve outcomes for the most immature infants,” the authors write.

Use of antenatal corticosteroids, an intervention recommended for improved neonatal outcomes, increased from 1993 to 2012 (24 percent to 87 percent), as did cesarean delivery (44 percent to 64 percent). Strategies to reduce lung injury, including less aggressive ventilation, are recommended. Delivery room intubation decreased from 80 percent in 1993 to 65 percent in 2012. Although most infants were ventilated, continuous positive airway pressure without ventilation increased from 7 percent in 2002 to 11 percent in 2012.

Despite no improvement from 1993 to 2004, rates of late-onset sepsis declined between 2005 and 2012 for infants of each gestational age. Rates of other complications declined, but bronchopulmonary dysplasia (a chronic lung disease developed after oxygen inhalation therapy or mechanical ventilation) increased between 2009 and 2012 for infants at 26 to 27 weeks’ gestation.

“The study provides a global overview and level of detail not presented in earlier studies. Findings demonstrate that progress is being made and outcomes of the most immature infants are improving,” the authors write. “These findings are valuable in counseling families and developing novel interventions.”

“Although survival of extremely preterm infants has increased over the past 2 decades, including survival without major morbidity, the individual and societal burden of preterm birth remains substantial, with approximately 450,000 neonates born prematurely in the United States each year. To truly affect newborn outcomes, a comprehensive and sustained effort to reduce the high rates of preterm birth is necessary.”

(doi:10.1001/jama.2015.10244; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Editorial: Progress in the Care of Extremely Preterm Infants

Roger F. Soll, M.D., of the University of Vermont College of Medicine, Burlington, comments on this study in an accompanying editorial.

“There is no obvious breakthrough therapy emerging in the coming years. Perhaps cellular therapy, such as mesenchymal stem cells, will be an important advance in the care of these fragile infants. However, it is more likely that incremental change, such as applying quality improvement practices to outcomes other than nosocomial infection, will lead to improved outcomes.”

“Stoll and colleagues have charted the progress made over the last 2 decades. It is clear that there are still a substantial number of extremely preterm infants who either die or survive after experiencing 1 or more major neonatal morbidities known to be associated with both short- and long-term adverse consequences. Although the neonatal-perinatal medicine community can be proud of the progress made, an additional commitment must be made to further improvements in the decades to come.”

(doi:10.1001/jama.2015.10911; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and reports receipt of personal fees (serving as president and member of the Board of Directors) from the Vermont Oxford Network outside the submitted work.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, SEPTEMBER 8, 2015

Media Advisory: To contact Martin N. Mwangi, Ph.D., email mart.mwangi@gmail.com. To contact editorial co-author Robert E. Black, M.D., M.P.H., call Stephanie Desmon at 410-955-7619 or email sdesmon1@jhu.edu.

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Among women in a malaria-endemic region in Kenya, daily iron supplementation during pregnancy did not result in an increased risk of malaria, according to a study in the September 8 issue of JAMA. Iron supplementation did result in increased birth weight, gestational duration, neonatal length, and a decreased risk of low birth weight and prematurity.

Anemia in pregnancy is a moderate or severe health problem in more than 80 percent of countries worldwide, but particularly in Africa, where it affects 57 percent of pregnant women. Iron deficiency is the most common cause, but iron supplementation during pregnancy has uncertain health benefits. There is some evidence to suggest that iron supplementation may increase the risk of infectious diseases, including malaria. Martin N. Mwangi, Ph.D., of Wageningen University, Wageningen, the Netherlands, and colleagues randomly assigned 470 pregnant Kenyan women living in a malaria endemic area to daily supplementation with 60 mg of iron (n = 237 women) or placebo (n = 233) until 1 month postpartum. All women received 5.7 mg iron/day through flour fortification during intervention and usual intermittent preventive treatment against malaria.

Among the 470 participating women, 40 women (22 iron, 18 placebo) were lost to follow-up or excluded at birth; 12 mothers were lost to follow-up postpartum (5 iron, 7 placebo). At study entry, 190 of 318 women (60 percent) were iron-deficient. The researchers found that in a comparison of women who received iron vs placebo, Plasmodium infection (malaria) prevalence after childbirth was 50.9 percent vs 52.1 percent. “Overall, we found no effect of daily iron supplementation during pregnancy on risk of maternal Plasmodium infection. Iron supplementation resulted in an increased birth weight [5.3 ounces], gestational duration, and neonatal length; enhanced maternal and infant iron stores at 1 month after birth; and a decreased risk of low birth weight (by 58 percent) and prematurity. The effect on birth weight was influenced by initial maternal iron status. Correction of maternal iron deficiency led to an increase in birth weight by [8.4 ounces].”

Serious adverse events were reported for 9 and 12 women who received iron and placebo, respectively.

The authors note that their results may apply to pregnant women in other low- and middle-income countries, although the effect on birth weight can vary depending on the prevalence of iron deficiency.

“In low- and middle-income countries, it is generally impractical to screen for iron status, and most countries have policies for universal iron supplementation for pregnant women. Based on our results, we believe that the benefits of universal supplementation outweigh possible risks.”

(doi:10.1001/jama.2015.9496; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Editorial: Antenatal Iron Use in Malaria Endemic Settings

“Pregnant women living in areas with endemic malaria require quality antenatal [during pregnancy] care,” write Parul Christian, Dr.P.H., M.Sc., and Robert E. Black, M.D., M.P.H., of the Johns Hopkins Bloomberg School of Public Health, Baltimore, in an accompanying editorial.

“In a recent evaluation using Demographic and Health Survey data from 41 countries, among women with 4 or more antenatal care visits, the greatest gaps in content of care involved iron and folic acid supplementation and malaria prevention. It is important that intermittent preventive treatment and insecticide-treated net use during pregnancy be increased in malaria endemic areas to protect the mother and fetus from the effects of malaria and to decrease the possible risk of adverse effects of iron if iron­ folic acid supplements or multiple micronutrient supplements are provided.”

(doi:10.1001/jama.2015.10032; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: Both authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, SEPTEMBER 8, 2015

Media Advisory: To contact Raj M. Ratwani, Ph.D., call Ann Nickels at 410-409-6399 or email ann.c.nickels@medstar.net.

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The lack of adherence to usability testing standards among several widely used electronic health record (EHR) products that were certified as having met these requirements may be a major factor contributing to the poor usability of EHRs, according to a study in the September 8 issue of JAMA.

Many EHRs have poor usability, leading to user frustration and safety risks. The U.S. Department of Health and Human Services’ Office of the National Coordinator for Health Information Technology (ONC) has established certification requirements to promote usability practices by EHR vendors as part of a meaningful use program. To develop a certified EHR, vendors are required to attest to using user-centered design (UCD), a process that places the needs of the frontline user at the forefront of software development, and to conduct formal usability testing on 8 different EHR capabilities to ensure the product meets performance objectives.

EHR vendors are required to provide a written statement naming the UCD process they used, and the results of their usability tests. The ONC has endorsed guidelines from the National Institute of Standards and Technology stipulating that usability testing should include at least 15 representative end-user participants, according to background information in the article.

Reports must be made public once the product is certified. Raj M. Ratwani, Ph.D., of MedStar Health, Washington, D.C., and colleagues analyzed reports meeting the 2014 certification requirements for the 50 EHR vendors with the highest number of providers (hospitals and small private practices) attesting to meeting meaningful use requirements with that product between April 2013 and November 2014. From each report, the authors extracted the stated UCD process and the number and clinical background of usability test participants.

Of the 50 certified vendor reports, 41 were available for review (82 percent); the remaining 9 (18 percent) were not publicly available. Of 41 vendors, 34 percent had not met the ONC certification requirement of stating their UCD process, 46 percent used an industry standard, and 15 percent used an internally developed UCD process.

There was variability in the number of participants enrolled in the usability tests. Of the 41 vendors, 63 percent used less than the standard of 15 participants and only 22 percent used at least 15 participants with clinical backgrounds. In addition, 1 of the 41 vendors used no clinical participants, 17 percent used no physician participants, and 5 percent used their own employees. Of the 41 vendor reports available, 12 percent lacked enough detail to determine whether physicians participated and 51 percent did not provide the required demographic details.

“The lack of adherence to usability testing may be a major factor contributing to the poor usability experienced by clinicians. Enforcement of existing standards, specific usability guidelines, and greater scrutiny of vendor UCD processes may be necessary to achieve the functional and safety goals for the next generation of EHRs,” the authors conclude.

(doi:10.1001/jama.2015.8372; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Fairbanks reported receiving grant support from the Agency for Healthcare Research and Quality. No other disclosures were reported.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, SEPTEMBER 1, 2015

Media Advisory: To contact George L. Bakris, M.D., call John Easton at 773-795-5225 or email John.easton@uchospitals.edu.

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Among patients with diabetes and kidney disease, most receiving an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker, the addition of the medication finerenone compared with placebo resulted in improvement in albuminuria (the presence of excessive protein [chiefly albumin] in the urine), according to a study in the September 1 issue of JAMA.

Diabetes mellitus is the most common cause of end-stage re­nal disease in the developed world. Trials of pa­tients with diabetic nephropathy (kidney disease from long-standing diabetes) have shown a strong relationship between magnitude of albuminuria reduction and slowing of chronic kidney disease (CKD) progression as well as reduced cardiovascular event rates. There is an unmet need to safely manage albuminuria with­out adversely affecting potassium levels in patients with type 2 diabetes mellitus who have a clinical diagnosis of diabetic kid­ney disease, according to information in the article.

George L. Bakris, M.D., of University of Chicago Medicine, and colleagues randomly assigned 823 patients (821 received study drug) with diabetes and elevated albuminuria who were receiving an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker to varying doses of the drug finerenone or placebo. In previous research, finerenone reduced albuminuria in pa­tients with chronic kidney disease and heart failure, with a lower incidence of hyperkalemia (higher than normal levels of potassium in the blood) compared to another medication. The current study was conducted at 148 sites in 23 countries.

At study entry, 37 percent of patients treated had very high albuminuria. The researchers found that finerenone reduced albuminuria at day 90 in a dose-dependent manner, with a significant reduc­tion in albuminuria (urinary albumin-creatinine ratio) ranging from 21 percent to 38 percent in the finerenone dos­age groups of 7.5 to 20 mg/d compared with placebo.

The outcome of hyperkalemia leading to discontinuation was not observed in the placebo and finerenone 10-mg/d groups; discontinuation in the finerenone 7.5-, 15-, and 20-mg/d groups were 2.1 percent, 3.2 percent, and 1.7 percent, respectively. There were no differences in the incidence of an estimated glomerular filtration rate (a measure of kidney function) decrease of 30 percent or more or in incidences of adverse events and serious adverse events between the placebo and finerenone groups.

“Further trials are needed to compare finerenone with other active medications,” the authors write.

(doi:10.1001/jama.2015.10081; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was funded by Bayer HealthCare AG. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, SEPTEMBER 1, 2015

Media Advisory: To contact Stephen W. Scherer, Ph.D., call Suzanne Gold at 416-813-7654, ext. 202059, or email Suzanne.gold@sickkids.ca. To contact editorial author Judith H. Miles, M.D., Ph.D., call Stephanie Baehman at 573-884-3650 or email baehmans@health.missouri.edu.

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The use of two newer genetic testing technologies (chromosomal microarray analysis and whole-exome sequencing) among children with autism spectrum disorder may help identify genetic mutations potentially linked to the disorder, according to a study in the September 1 issue of JAMA. The study also found that children with certain physical anomalies were more likely to have genetic mutations, findings that may help identify children who could benefit most from genetic testing.

Autism spectrum disorder (ASD) represents a diverse group of neurodevelopmental conditions. The clinical presentation and outcome vary substantially. The use of genome-wide tests to provide molecular diagnosis for individuals with ASD requires more study, according to background information in the article.

Stephen W. Scherer, Ph.D., of the Hospital for Sick Children, Toronto, and colleagues performed chromosomal microarray analysis (CMA) and whole-exome sequencing (WES) in a group of 258 unrelated children with ASD to determine the molecular diagnostic yield (the percentage of subjects with a genetic alteration [mutation] that may contribute to the features of autism spectrum disorder) of these tests. All children underwent CMA; a random subset of 95 also underwent WES. All children underwent detailed clinical assessments for the presence of any major congenital abnormalities and minor physical anomalies and were stratified into 3 groups of increasing morphological severity (physical aberrations): essential, equivocal, and complex.

Of the 258 children, 24 (9.3 percent) received a molecular diagnosis from CMA and 8 of 95 (8.4 percent) from WES. The yields were statistically different between the morphological groups. Among the children who underwent both CMA and WES testing, the estimated proportion with an identifiable genetic cause was 15.8 percent. This included 2 children who received molecular diagnoses from both tests. The clinical yield for genetic testing was much higher (37.5 percent) in children with ASD who had more complex clinical presentations based on physical examination.

“In the current study, we have demonstrated differences related to morphological stratification of ASD [children] based on clinical examination. Our data suggest that medical evaluation of ASD children may help identify populations more likely to achieve a molecular diagnosis with genetic testing,” the authors write.

“It seems likely that genetic testing of children with ASD will continue to increase. In a survey of parental interest in ASD genetic testing, 80 percent of parents indicated that they would want a sibling younger than 2 years tested to identify ASD-risk mutations even if the test could not confirm or rule out the diagnosis. For some children with positive genetic test results, treatment plans targeting ASD-associated medical conditions can be offered.”

The researchers conclude that if “replicated in additional populations, these findings may inform appropriate selection of molecular diagnostic testing for children affected by ASD.”

(doi:10.1001/jama.2015.10078; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Editorial: Complex Autism Spectrum Disorders and Cutting-Edge Molecular Diagnostic Tests

“For ASD, as well as for other behaviorally defined disorders, the results reported by Tammimies et al provide clear guidance,” writes Judith H. Miles, M.D., Ph.D., of University of Missouri Health Care, Columbia, in an accompanying editorial.

“Foremost, the data indicate that physicians responsible for children with ASD should arrange access to a genetic evaluation using techniques that have the best chance of determining an etiologic diagnosis. It is incontrovertible that precise diagnoses pave the way to better medical care, improved surveillance, better functional outcomes, and informed genetic counseling, often with the possibility of prenatal or preimplantation diagnosis.”

(doi:10.1001/jama.2015.9577; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, SEPTEMBER 1, 2015

Media Advisory: To contact Jonathan Rosand, M.D., M.Sc., call Terri Ogan at 617-726-0954 or email togan@partners.org.

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Survivors of an intracerebral hemorrhage (ICH; a type of hemorrhagic stroke in which bleeding occurs directly into the brain) who had inadequate blood pressure (BP) control during follow-up had a higher risk of ICH recurrence, with this association appearing stronger with worsening severity of hypertension, according to a study in the September 1 issue of JAMA.

Intracerebral hemorrhage is the most severe and least treatable form of stroke, respon­sible for almost 50 percent of stroke-related illness and death. Intracerebral hemorrhage survivors are at high risk for recurrent ICH, death, and worsening disability. Preliminary evidence from another study suggested that BP lowering reduces incidence of ICH, according to background information in the study.

Jonathan Rosand, M.D., M.Sc., of Massachusetts General Hospital, Boston, and colleagues sought to determine whether BP reduc­tion and control are associated with risk of recurrence of lobar (a particular region of the brain) or nonlobar ICH. The study included 1,145 patients with ICH who survived at least 90 days and were followed up through December 2013 (median follow-up of 37 months). Blood pressure measurements were obtained at 3, 6, 9, and 12 months, and every 6 months thereafter from medical personnel or patient self-report.

There were 102 recurrent ICH events among 505 survivors of lobar ICH and 44 recurrent ICH events among 640 survivors of nonlobar ICH. During follow-up, adequate BP control (based on American Heart Association/American Stroke Association recommendations) was achieved on at least 1 measurement by 625 patients (55 percent of total) and consistently (i.e., at all available time points) by 495 patients (43 percent of total). The researchers found that the ICH event rate for lobar and nonlobar ICH was higher among patients with inadequate BP control compared with patients with adequate BP control. Analyses indicated that inadequate BP control was associated with higher risk of recurrence of both lobar and nonlobar ICH. The association between el­evated BP and ICH recurrence appeared to become stronger with worsening severity of hypertension.

Systolic BP during follow-up was associated with increased risk of both lobar and nonlobar ICH recurrence. Diastolic BP was associated with increased risk of nonlobar ICH recurrence, but not with lobar ICH recurrence.

“These results confirm that ICH survivors are at high risk for re­currence and support the hypothesis that aggressive blood pressure control may reduce this risk substantially,” the authors write. They add that the findings suggest that randomized clinical trials are needed to address the ben­efits and risks of stricter BP control in ICH survivors.

(doi:10.1001/jama.2015.10082; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The authors’ work on this study was supported by funding from the National Institute of Neurological Disorders and Stroke. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, SEPTEMBER 1, 2015

Media Advisory: To contact Arul M. Chinnaiyan, M.D., Ph.D., call Nicole Fawcett at 734-764-2220 or email nfawcett@umich.edu. To contact editorial co-author John M. Maris, M.D., call Alison Fraser at 267-426-6054 or email frasera1@email.chop.edu.

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In a study that included children and young adults with relapsed or refractory cancer, incorporation of integrative clini­cal genomic sequencing data into clinical management was feasible, re­vealed potentially actionable findings in nearly half of the patients, and was associated with change in treatment and family genetics counseling for a small proportion of patients, according to a study in the September 1 issue of JAMA.

Outcomes of children and young adults with cancer have improved, primarily due to enhanced understanding of tumor biology and due to the clinical application of biological discoveries through multicenter clinical trials. However, survival for many pediatric oncology pa­tients, including those with recurrent disease or metastatic dis­ease, remains poor. Advances in genomic sequencing technologies have improved the ability to detect molecular aberrations with greater sensitivity and to identify genomic alterations that can be matched to targeted therapies. However, integrating this data into clinical management in an individualized manner has proven challenging, according to background information in the article.

Arul M. Chinnaiyan, M.D., Ph.D., of the University of Michigan, Ann Arbor, and colleagues studied104 children and young adults (average age, 11 years) with relapsed, refractory, or rare cancer. Participants underwent integrative clinical exome (tumor and germline DNA) and transcriptome (tumor RNA) sequencing and genetic counseling. Results were discussed by a precision medicine tumor board, which made recommendations to families and their physicians.

Of the 104 screened patients, 102 enrolled with 91 (89 percent) having adequate tumor tissue to complete sequencing. Only the 91 patients were included in all calculations, including 28 (31 percent) with hematological malignancies and 63 (69 percent) with solid tumors. Forty-two patients (46 percent) had actionable findings that changed cancer management: 15 of 28 (54 percent) with hematological malignancies and 27 of 63 (43 percent) with solid tumors. Individualized actions were taken in 23 of the 91 (25 percent) based on clinical sequencing findings, including change in treatment for 14 patients (15 percent) and genetic counseling for 9 patients (10 percent).

Nine of 91 (10 percent) of the personalized clinical interventions resulted in ongoing partial clinical remission of 8 to 16 months or helped sustain complete clinical remission of 6 to 21 months. All 9 patients and families with actionable incidental genetic findings agreed to genetic counseling and screening.

“Many of these families had no significant family history and would likely have not been referred to genetic counseling under routine clinical care,” the authors write.

The researchers note that the lack of a control group limited assessing whether better clinical outcomes resulted from integrative clini­cal sequencing than outcomes that would have occurred with standard care.

(doi:10.1001/jama.2015.10080; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Editorial: Improving Patient Outcomes With Cancer Genomics

John M. Maris, M.D., of Children’s Hospital of Philadelphia, and colleagues comment on this study in an accompanying editorial.

“The study by Mody and colleagues represents an impor­tant contribution to the care of children with cancer. It makes clear that approaches that are rapidly evolving in adults are ap­plicable to the care of children with cancer. These data strongly suggest that precision medicine enhanced by genetic evalua­tion may improve the outcomes of children with cancer.”

(doi:10.1001/jama.2015.9794; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, SEPTEMBER 1, 2015

Media Advisory: To contact Benjamin N. Breyer, M.D., M.A.S., call Elizabeth Fernandez at 415-514-1592 or email Elizabeth.Fernandez@UCSF.edu.

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Between 1998 and 2013, there was a large increase in bicycle-related injuries and hospital admissions of adults in the United States, with the increase in injuries driven by more injuries among adults older than 45 years of age, according to a study in the September 1 issue of JAMA.

Cycling is associated with many health benefits, but also with the risk of injury. Trends in bicycle-related injuries are difficult to assess because the majority of nonfatal injuries sustained while cycling are not reported to police and thus are not included in traffic statistics. Benjamin N. Breyer, M.D., M.A.S., of the University of California, San Francisco, and colleagues analyzed data from the National Electronic Injury Surveillance System (NEISS), a national probability sample of approximately 100 emergency departments that gathers product-related injury data. The researchers queried the NEISS for injuries associated with bicycles from 1998 to 2013. The number of bicycle-related injuries in adults age 18 years or older was recorded in 2-year intervals.

During the study period, the 2-year age-adjusted incidence of injuries increased by 28 percent; the incidence of hospital admissions increased by 120 percent. The percentage of injured cyclists with head injuries increased from 10 percent to 16 percent. Overall, 35 percent of injuries occurred in women, with no significant change in sex ratio of injuries over time.

The proportion of injuries occurring in individuals older than 45 years increased 81 percent, from 23 percent to 42 percent, and the proportion of hospital admissions in individuals older than 45 years increased 66 percent, from 39 percent to 65 percent. “These injury trends likely reflect the trends in overall bicycle ridership in the United States in which multiple sources show an increase in ridership in adults older than 45 years,” the authors write.

“Other possible factors contributing to the increase in overall injuries and hospital admissions include an increase in street accidents and an increase in sport cycling associated with faster speeds. As the population of cyclists in the United States shifts to an older demographic, further investments in infrastructure and promotion of safe riding practices are needed to protect bicyclists from injury.”

(doi:10.1001/jama.2015.8295; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 7:45 A.M. (ET) SUNDAY, AUGUST 30, 2015

Media Advisory: To contact Gregory Y. H Lip, M.D., email g.y.h.lip@bham.ac.uk.

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Among patients with heart failure with or without atrial fibrillation, use of a common clinical risk score was associated with risk of ischemic stroke, thromboembolism (blood clot), and death; however, predictive accuracy was modest, and the clinical usefulness of this score in patients with heart failure remains to be determined, according to a study appearing in JAMA. The study is being released to coincide with its presentation at the European Society of Cardiology Congress 2015.

Heart failure (HF) is associated with an increased risk of ischemic stroke and death. Risk stratification using readily available clinical variables may help identify sub­groups at low and high risk of ischemic stroke and thromboembolic events (TE) in an HF population. The CHA₂DS₂-VASc score (congestive heart failure, hypertension, age 75 years or older [doubled], diabetes, stroke/transient ischemic attack/thromboembolism [doubled], vascular disease [prior heart attack, peripheral artery disease, or aortic plaque], age 65-75 years, sex category [female]) is already used clinically for stroke risk stratification in patients with atrial fibrillation (AF). Its usefulness in a population of patients with HF has been unclear, according to background information in the article.

Gregory Y. H Lip, M.D., of Aalborg University, Aalborg, Denmark, and colleagues investigated whether CHA₂DS₂-VASc predicts ischemic stroke, thromboembolism, and death within one year in patients with a new diagnosis of HF with and without AF. Using Danish registries, the study included 42,987 patients (22 percent with concomitant [accompanying] AF) not receiving anticoagulation who were diagnosed as having new onset HF during 2000-2012. End of follow-up was December 31, 2012. Levels of the CHA₂DS₂-VASc score (based on 10 possible points, with higher scores indicating higher risk) were stratified by presence of AF at study entry.

The researchers found that pa­tients with HF had a high risk of ischemic stroke, TE, and death whether or not AF was present. However, the CHA₂DS₂-VASc score was only modestly able to predict these outcomes. At high CHA₂DS₂-VASc scores, patients with HF without AF had high absolute risk of ischemic stroke, TE, and death, and the absolute risk increased in a comparable manner in patients with HF, with and without AF. The absolute risk of thromboembolic com­plications was higher among patients without AF compared with patients with concomitant AF with high CHA₂DS₂-VASc scores.

“The poor progno­sis of AF for ischemic stroke and death in patients with HF was evident in our study, but the observation that additional risk factors in patients with HF are particularly significant among those without AF is an important result. Indeed, preventa­tive strategies to reduce ischemic stroke and TE risk in this large patient population require further investigation,” the authors write.

(doi:10.1001/jama.2015.10725; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, AUGUST 25, 2015

Media Advisory: To contact Kaycee M. Sink, M.D., M.A.S., call Marguerite Beck at 336-716-2415 or email marbeck@wakehealth.edu. To contact Emily Y. Chew, M.D., call Joe Balintfy at 301-496-5248 or email neinews@nei.nih.gov. To contact editorial co-author Sudeep S. Gill, M.D., M.Sc., email Anne Craig at anne.craig@queensu.ca.

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Two studies in the August 25 issue of JAMA examine the effect of physical activity and nutrient supplementation on cognitive function.

In one study, Kaycee M. Sink, M.D., M.A.S., of the Wake Forest School of Medicine, Winston-Salem, N.C., and colleagues evaluated whether a 24-month physical activity program would result in better cognitive function, lower risk of mild cognitive impairment (MCI) or dementia, or both, compared with a health education program.

Epidemiological evidence suggests that physical activity is associated with lower rates of cognitive decline. Exercise is associated with improved cerebral blood flow and neuronal connectivity and maintenance or improvement in brain volume. However, evidence from randomized trials has been limited and mixed, according to background information in the article.

Participants in the Lifestyle Interventions and Independence for Elders (LIFE) study (n = 1,635; 70 to 89 years of age) were randomly assigned to a structured, moderate-intensity physical activity program (n = 818) that included walking, resistance training, and flexibility exercises or a health education program (n = 817) of educational workshops and upper-extremity stretching. Participants were sedentary adults who were at risk for mobility disability but able to walk about a quarter mile.  Measures of cognitive function and incident MCI or dementia were determined at 24 months.

The researchers found that the moderate-intensity physical activity intervention did not result in better global or domain-specific cognition compared with the health education program. There was also no significant difference between groups in the incidence of MCI or dementia (13.2 percent in the physical activity group vs 12.1 percent in the health education group), although this outcome had limited statistical power.

“Cognitive function remained stable over 2 years for all participants. We cannot rule out that both interventions were successful at maintaining cognitive function,” the authors write.

Participants in the physical activity group who were 80 years or older and those with poorer baseline physical performance had better changes in executive function composite scores compared with the health education group. “This finding is important because executive function is the most sensitive cognitive domain to exercise interventions, and preserving it is required for independence in instrumental activities of daily living. Future physical activity interventions, particularly in vulnerable older adult groups (e.g., ≥80 years of age and those with especially diminished physical functioning levels), may be warranted.”

(doi:10.1001/jama.2015.9617; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

In another study, Emily Y. Chew, M.D., of the National Eye Institute/National Institutes of Health, Bethesda, Md., and colleagues tested the effects of oral supplementation with nutrients on cognitive function.

The prevalence of Alzheimer disease, estimated to have affected 5.2 million people in the United States in 2013, may triple in the next 4 decades. Epidemiologic studies have suggested that diets high in omega-3 long-chain polyunsaturated fatty acids (LCPUFAs) have a protective role in maintaining cognitive function. However, numerous randomized clinical trials (RCTs) failed to show omega-3 LCPUFAs to be effective in treating dementia, according to background in the article.

Participants in the Age-Related Eye Disease Study 2 [AREDS2]), who were at risk for developing late age-related macular degeneration (AMD), were randomly assigned to LCPUFAs (1 g) and/or the dietary supplements lutein (10 mg)/zeaxanthin (2 mg) vs placebo. All participants were also given varying combinations of vitamins C. E. beta carotene, and zinc. In addition to annual eye examinations, several validated cognitive function tests were administered via telephone by trained personnel at baseline and every 2 years during the 5-year study. A total of 89 percent (3,741/4,203) of AREDS2 participants consented to the ancillary cognitive function study and 94 percent (3,501/3,741) underwent cognitive function testing. The average age of the participants was 73 years, and 57.5 percent were women.

There were no statistically significant differences in change of measures of cognitive function for participants randomized to receive supplements vs those who were not. The yearly change in the composite cognitive function score was -0.19 for participants randomized to receive LCPUFAs vs -0.18 for those randomized to no LCPUFAs. Similarly, the yearly change in the composite cognitive function score was -0.18 for participants randomized to receive lutein/zeaxanthin vs -0.19 for those randomized to not receive lutein/zeaxanthin.

Regarding the lack of effect of the supplements, the authors speculate that the supplements were started too late in the aging process and that supplementation duration of 5 years may be insufficient. “The process of cognitive decline may occur over decades, thus a short-term supplementation given too late in the disease may not be effective.”

They add that the observational data regarding dietary intake of specific nutrients such as omega-3 LCPUFAs and antioxidants suggest strong inverse associations with dementia, yet the RCTs have failed to show beneficial effects. “It is possible that eating foods rather than taking any specific single supplement may have an effect.”

(doi:10.1001/jama.2015.9677; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Editorial: Lifestyles and Cognitive Health

“Although the well-designed RCTs presented by Sink and colleagues and Chew and colleagues failed to demonstrate significant cognitive benefits, these results should not lead to nihilism involving lifestyle factors in older adults. It is still likely that lifestyle factors such as diet and physical activity have important roles in the prevention of cognitive decline, dementia, and performance of the activities of daily living,” write Sudeep S. Gill, M.D., M.Sc., and Dallas P. Seitz, M.D., Ph.D., of Queen’s University, Kingston, Ontario, Canada, in an accompanying editorial.

“Physicians should encourage patients of all ages to optimize physical activity levels throughout their life, which may help to reduce the risk of developing dementia and many other adverse health outcomes. An active lifestyle throughout the lifespan may be more effective in preventing cognitive decline than starting physical activity after the onset of cognitive symptoms. Similarly, adherence to Mediterranean or heart healthy diets throughout life are likely to be most beneficial in preventing cognitive decline or the onset of dementia in contrast to isolated nutritional supplements initiated late in life.”

(doi:10.1001/jama.2015.9526; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, AUGUST 25, 2015

Media Advisory: To contact Michael W. Donnino, M.D., call Kelly Lawman at 617-667-7305 or email klawman@bidmc.harvard.edu. To contact editorial co-author Adrienne G. Randolph, M.D., M.Sc., call Kristen Dattoli at 617-919-3110 or email kristen.dattoli@childrens.harvard.edu.

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Among children with in-hospital cardiac arrest with an initial nonshockable heart rhythm who received epinephrine (adrenaline), delay in administration of epinephrine was associated with a decreased chance of 24-hour survival and survival to hospital discharge, according to a study in the August 25 issue of JAMA.

Approximately 16,000 children in the United States have a cardiac arrest each year, predominantly in a hospital setting. Epinephrine is recommended by both the American Heart Association and the European Resuscitation Council in pediatric cardiac arrest. Delay in administration of the first epinephrine dose is associated with decreased survival among adults after in-hospital, nonshockable (pulseless electrical activity or asystole) cardiac arrest. Whether this association is the same for children has not been known, according to background information in the article.

Michael W. Donnino, M.D., of Beth Israel Deaconess Medical Center, Boston, and colleagues examined whether time to first epinephrine dose is associated with improved clinical outcomes in pediatric in-hospital cardiac arrest. The researchers performed an analysis of data from the Get With the Guidelines–Resuscitation registry and included U.S. pediatric patients (age <18 years) with an in-hospital cardiac arrest and an initial nonshockable rhythm who received at least 1 dose of epinephrine.

A total of 1,558 patients (median age, 9 months) were included in the final analysis. Among these patients, 487 (31 percent) survived to hospital discharge. The median time to first epinephrine dose was 1 minute. Delay in administration of epinephrine was associated with a decreased chance of return of spontaneous circulation (ROSC), 24-hour survival, survival to hospital discharge, and survival to hospital discharge with a favorable neurological outcome. These associations remained when accounting for multiple patient, event, and hospital characteristics.

Patients with time to epinephrine administration of longer than 5 minutes (233/1,558) compared with those with time to epinephrine of 5 minutes or less (1,325/1,558) had lower likelihood of in-hospital survival to discharge (21 percent vs 33.1 percent).

“Although the observational design precludes ascertainment of causality, the strong association with outcomes suggests that early epinephrine may be beneficial in pediatric cardiac arrest,” the authors write.

(doi:10.1001/jama.2015.8950; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Editorial: Pediatric Pulseless Arrest With “Nonshockable” Rhythm

“The study by Andersen et al reinforces that pediatric patients with in-hospital cardiac arrest and nonshockable rhythms have poor overall prognosis: less than one-third survive to hospital discharge, and survival with favorable neurocognitive outcome was even lower, at best 17 percent, even when epinephrine was given within first 5 minutes of resuscitation,” write Robert C. Tasker, M.B.B.S., M.D., and Adrienne G. Randolph, M.D., M.Sc., of Boston Children’s Hospital, in an accompanying editorial.

“Given there will never be a randomized clinical trial and that epinephrine is listed in the pediatric advanced life support guidelines as the next step after CPR for nonshockable rhythms, these new data provide fairly strong evidence that following the guidelines with regards to epinephrine dosing and timing is best practice, with this study likely providing an AHA Class I strength of recommendation. The data support what is currently recommended and show some benefit in the first 5 minutes. It is not known if epinephrine should be given within 2 minutes, as a good number of patients did not receive the drug at all and had ROSC in that time.”

(doi:10.1001/jama.2015.9527; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Both authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, AUGUST 25, 2015

Media Advisory: To contact Adi V. Gundlapalli, M.D., Ph.D., M.S., call Jill Atwood at 801-584-1252 or email Jill.atwood@va.gov.

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Among U.S. veterans who returned from Afghanistan and Iraq, being separated from the military for misconduct was associated with an increased risk of homelessness, according to a study in the August 25 issue of JAMA.

Adi V. Gundlapalli, M.D., Ph.D., M.S., of the VA Salt Lake City Health Care System, Salt Lake City, and colleagues analyzed Veterans Health Administration (VHA) data from U.S. active-duty military service members who were separated (end date of last deployment) from the military between October 2001 and December 2011, deployed in Afghanistan or Iraq, and eligible for and subsequently used VHA services. Homelessness was determined by a coding assignment of “lack of housing” during a VHA encounter, by participation in a VHA homelessness program, or both. The U.S. Department of Defense assigns a code upon separation from military service. These codes were categorized into misconduct (drugs, alcoholism, offenses, infractions, other), disability, early release, disqualified, normal, and other or unknown.

The analysis included 448,290 active-duty service members separated during this time period. Homelessness was determined by code (43 percent), participation in a homelessness program (35 percent), or both (27 percent). Although only 6 percent (n = 24,992) separated for misconduct, they represented 26 percent of homeless veterans at first VHA encounter (n = 322), 28 percent within 1 year (n = 1,141), and 21 percent within 5 years (n = 709). Incidence of homelessness was significantly greater for misconduct vs normal separations at first VHA encounter (1.3 percent vs 0.2 percent) and increased with time since first VHA encounter: within 1 year (5.4 percent vs 0.6 percent);  at 5 years (9.8 percent vs 1.4 percent).

The authors write that these findings support reports of recently returned veterans with records of misconduct having difficulties reentering civilian life. “This association takes on added significance because the incidence of misconduct-related separations is increasing at a time when ending homelessness among veterans is a federal government priority.”

“Identification of those with misconduct-related separations and provision of case management and rehabilitative services at separation by the Department of Defense and the VHA should be investigated as methods to prevent homelessness.”

(doi:10.1001/jama.2015.8207; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, AUGUST 25, 2015

Media Advisory: To contact Timothy J. Ley, M.D., call Diane Duke Williams at 314-286-0111 or email williamsdia@wustl.edu. To contact editorial co-author Ross L. Levine, M.D., call Nicole McNamara at 646-227-3633 or email mcnamarn@mskcc.org. An author interview podcast also will be available when the embargo lifts on the JAMA website: http://bit.ly/1NKdoAj

To place an electronic embedded link to this study and editorial in your story  This link to the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.9643 This will be the link to the editorial: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.9452

In preliminary research, the detection of persistent leukemia-associated genetic mutations in at least 5 percent of bone marrow cells in day 30 remission samples among adult patients with acute myeloid leukemia was associated with an increased risk of relapse and reduced overall survival, according to a study in the August 25 issue of JAMA.

Approximately 20 percent of adult patients with acute myeloid leukemia (AML) fail to achieve remission with initial induction chemotherapy, and approximately 50 percent ultimately experience relapse after achieving complete remission. Even though potentially curative therapy (e.g., allogeneic hematopoietic stem cell transplantation) is now available for many patients, this therapy is expensive and is associated with significant side effects. Identifying patients at high risk for relapse would be helpful clinically, according to background information in the article.

Timothy J. Ley, M.D., of the Washington University School of Medicine, St. Louis, and colleagues sought to determine whether genomic approaches can provide prognostic information for adult patients with AML. Whole-genome or exome sequencing was performed on samples obtained at disease presentation from 71 patients with AML (average age, 51 years) treated with standard induction chemotherapy at a single center starting in March 2002, with follow-up through January 2015. In addition, deep digital sequencing (next generation sequencing that permits sequencing of hundreds to thousands of individual molecules of DNA) was performed on paired diagnosis and remission samples from 50 patients (including 32 with intermediate-risk AML), approximately 30 days after successful induction therapy. Twenty-five of the 50 were from the cohort of 71 patients, and 25 were new, additional cases.

Analysis of comprehensive genomic data from the 71 patients did not improve outcome assessment over current standard-of-care metrics. In an analysis of 50 patients with both presentation and documented remission samples, 24 (48 percent) had persistent leukemia-associated mutations (mutations that are known to exist in a leukemia sample when the patient presents with the disease, but are not cleared after the initial chemotherapy is given, and the bone marrow recovers) in at least 5 percent of bone marrow cells at remission. The 24 with persistent mutations had significantly reduced event-free (6 vs. 17.9 months) and overall survival (10.5 vs. 42.2 months) vs the 26 who cleared all mutations (leukemia specific mutations that are found in the presentation sample that are completely eliminated after initial chemotherapy). These associations also were found among the 32 AML cases with intermediate risk cytogenetics (a risk classification category for AML based on looking at the tumor cell’s chromosomes).

“The data presented in this report begin to define a genomic method for the risk stratification of patients with AML that places greater emphasis on the clearance of somatic mutations [mutations that are not inherited] after chemotherapy than the identification of specific mutations at the time of presentation,” the authors write. “Although this study was not designed to determine the optimal clearance threshold for the association with outcomes, it represents a foundation for prospective trials focused on the role of digital sequencing to improve risk stratification for AML patients, and perhaps other cancer types as well.”

(doi:10.1001/jama.2015.9643; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Editorial: Next-Generation Sequencing and Detection of Minimal Residual Disease in Acute Myeloid Leukemia

Friederike Pastore, M.D., and Ross L. Levine, M.D., of the Memorial Sloan Kettering Cancer Center, New York City, comment on the findings of this study in an accompanying editorial.

“Although many important questions remain, the findings reported by Klco and colleagues provide critical insights into the role of molecular monitoring in AML and into the dynamics of genetic mutations during AML treatment. The next steps should involve development of assays that can be used to enumerate minimal residual disease (MRD) in the clinic, performance studies to enumerate how best to use MRD monitoring in clinical care, and formulation of therapeutic regimens to target MRD and eradicate mutant clones to improve outcomes for patients with AML.”

(doi:10.1001/jama.2015.9452; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Both authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Pastore reports receiving a grant from the German Research Foundation. No other disclosures were reported.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, AUGUST 18, 2015

Media Advisory: To contact Adam M. Leventhal, Ph.D., call Leslie Ridgeway at 323-442-2823 or email lridgewa@usc.edu. To contact editorial author Nancy A. Rigotti, M.D., call Mckenzie Ridings at 617-726-0274 or email mridings@mgh.harvard.edu. To contact Viewpoint co-author Michele Barry, M.D., call Rosanne Spector at 650-725-5374 or email manishma@stanford.edu.

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Among high school students in Los Angeles, those who had ever used electronic cigarettes were more likely to report initiation of smokable (“combustible”) tobacco (such as cigarettes, cigars, and hookah) use over the next year compared with nonusers, according to a study in the August 18 issue of JAMA.

Combustible tobacco, which has well-known health consequences, has long been the most common nicotine-delivering product used. Electronic cigarettes (e-cigarettes), which are devices that deliver inhaled aerosol usually containing nicotine, are becoming increasingly popular, particularly among adolescents, including teens who have never used combustible tobacco. According to 2014 U.S. estimates, 16 percent of 10th graders reported use of e-cigarettes within the past 30 days, of whom 43 percent reported never having tried combustible cigarettes. Whether use of e-cigarettes is associated with risk of initiating combustible tobacco use has not been known, according to background information in the article.

Adam M. Leventhal, Ph.D., of the Keck School of Medicine of the University of Southern California, Los Angeles, and colleagues examined whether adolescents who reported ever using e-cigarettes were more likely to initiate the use of combustible tobacco (cigarettes, cigars, and hookah) during the subsequent year. The study included 2,530 students from ten public high schools in Los Angeles who reported never using combustible tobacco at study entry (fall 2013, 9th grade, average age = 14 years) and completed follow-up assessments at 6 months (spring 2014, 9th grade) or 12 months (fall 2014, 10th grade). At each time point, students completed self-report surveys on any use of combustible tobacco products.

The researchers found that e-cigarette users (n = 222) were more likely than never users (n = 2,308) to report past 6-month use of any combustible tobacco product at the 6-month follow-up (31 percent vs 8 percent) and at the 12-month follow-up (25 percent vs 9 percent). Baseline e-cigarette use was associated with a greater likelihood of use of any combustible tobacco product averaged across the 2 follow-up periods in the analyses adjusted for sociodemographic, environmental, and intrapersonal risk factors for smoking. In addition, relative to baseline e-cigarette never users, e-cigarette ever users were more likely to be using at least 1 more combustible tobacco product averaged across the 2 follow-up assessments.

“These data provide new evidence that e-cigarette use is prospectively associated with increased risk of combustible tobacco use initiation during early adolescence. Associations were consistent across unadjusted and adjusted models, multiple tobacco product outcomes, and various sensitivity analyses,” the authors write.

They add that “some teens may be more likely to use e-cigarettes prior to combustible tobacco because of beliefs that e-cigarettes are not harmful or addictive, youth-targeted marketing, availability of e-cigarettes in flavors attractive to youths, and ease of accessing e-cigarettes due to either an absence or inconsistent enforcement of restrictions against sales to minors.”

“Further research is needed to understand whether this association may be causal.”

(doi:10.1001/jama.2015.8950; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This research was supported by grants from the National Institutes of Health. The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Editorial: E-Cigarette Use and Subsequent Tobacco Use by Adolescents

The report by Leventhal and colleagues is the strongest evidence to date that e-cigarettes might pose a health hazard by encouraging adolescents to start smoking conventional tobacco products, writes Nancy A. Rigotti, M.D., of Massachusetts General Hospital and Harvard Medical School, Boston,

“Regardless of whether e-cigarettes are a gateway to tobacco product initiation, there is no reason for adolescents to use a product for which the hypothesized public health benefit is harm reduction for adult smokers. However, there is ample evidence that e-cigarettes are marketed in ways that appeal to children and adolescents. Prompt, effective action is needed to protect youth and reduce the demand for e-cigarettes by nonsmokers of all ages. A rational approach is to extend to e-cigarettes the same sales, marketing, and use restrictions that apply to combustible cigarettes.”

(doi:10.1001/jama.2015.8382; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including financial disclosures, funding and support, etc.

Related Viewpoint: The Global Health Implications of e-Cigarettes

In an accompanying Viewpoint, Andrew Y. Chang, M.D., and Michele Barry, M.D., of the Stanford University School of Medicine, Stanford, Calif., discuss health considerations of e-cigarettes unique to low- and middle-income countries.

“Developing nations should not underestimate the availability and targeted marketing of electronic nicotine delivery systems (ENDS) within their borders and should place e-cigarettes under the purview of their medical and pharmaceutical regulatory boards. Low- and middle-income countries can feel empowered to exclude multinational tobacco companies from this regulatory process in accordance with Article 5.3 of WHO’s Framework Convention on Tobacco Control, which warns against the conflict of interest posed by the industry in this sphere.”

“International nongovernmental organizations such as the Gates Foundation and the Bloomberg Initiative to Reduce Tobacco Use should support these efforts to provide consistency in control and enforcement of ENDS legislation. Even though e-cigarettes may have a future as smoking cessation tools, evidence to support this indication is lacking. More rigorous studies must be conducted regarding the awareness, usage patterns, and potential for harm of these devices in low-income countries, particularly Africa and South Asia, where data are currently missing.”

(doi:10.1001/jama.2015.8676; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, AUGUST 18, 2015

Media Advisory: To contact Melanie J. Davies, M.D., email melanie.davies@uhl-tr.nhs.uk.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.9676

Among overweight and obese patients with type 2 diabetes, daily injection of the diabetes drug liraglutide with a modified insulin pen device, in addition to diet and exercise, resulted in greater weight loss over 56 weeks compared with placebo, according to a study in the August 18 issue of JAMA.

Obesity is a chronic disease and a significant global health challenge. Weight loss is recommended for patients with type 2 diabetes. Moderate weight loss (5 percent-10 percent) can improve glycemic control and other cardiometabolic risk factors and disorders. Weight loss is especially challenging for individuals with type 2 diabetes, who often experience a reduced response to weight-management pharmacotherapies compared with individuals without diabetes. Liraglutide is a medication approved for the treatment of type 2 diabetes (administered once daily at doses of 1.2 mg and 1.8 mg). Weight loss has also been observed with liraglutide at these doses, according to background information in the article.

Melanie J. Davies, M.D., of the University of Leicester, United Kingdom, and colleagues randomly assigned 846 overweight or obese study participants (age 18 years or older) with type 2 diabetes to once-daily injections of liraglutide (3.0 mg) (n = 423), liraglutide (1.8 mg) (n = 211), or placebo (n = 212) for 56 weeks. A 12-week “off-drug” follow-up period was included to assess treatment-cessation effects (total study length, 68 weeks). The study was conducted at 126 sites in 9 countries between June 2011 and January 2013. Participants were also instructed to follow a reduced-calorie diet and increase physical activity for weight management.

Average weight loss was 6.0 percent (14.1 lbs.) with liraglutide (3.0-mg dose), 4.7 percent (11 lbs.) with liraglutide (1.8-mg dose), and 2.0 percent (4.8 lbs.) with placebo. Weight loss of 5 percent or greater occurred in 54.3 percent with liraglutide (3.0 mg) and 40.4 percent with liraglutide (1.8 mg) vs 21.4 percent with placebo. Weight loss greater than 10 percent occurred in 25.2 percent with liraglutide (3.0 mg) and 15.9 percent with liraglutide (1.8 mg) vs 6.7 percent with placebo. More gastrointestinal disorders were reported with liraglutide (3.0 mg) vs liraglutide (1.8 mg) and placebo. Pancreatitis was not reported.

“To our knowledge, this is the first study specifically designed to investigate the efficacy of liraglutide for weight management in patients with type 2 diabetes and also the first study to investigate liraglutide at the higher 3.0-mg dose in a population with type 2 diabetes,” the authors write. “In the present trial, liraglutide (3.0 mg), as an adjunct to a reduced-calorie diet and increased physical activity, was effective and generally well tolerated and was significantly better than placebo on all 3 co-primary weight-related end points.”

“Further studies are needed to evaluate longer-term efficacy and safety.”

(doi:10.1001/jama.2015.9676; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was funded by Novo Nordisk. Liraglutide is a Novo Nordisk A/S proprietary compound. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, AUGUST 18, 2015

Media Advisory: To contact Agnes Y. Y. Lee, M.D., M.Sc., call Heather Amos at 604-822-3213 or email heather.amos@ubc.ca.

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Among patients with active cancer and acute symptomatic venous thromboembolism (VTE; blood clots in the deep veins), the use of the low molecular-weight heparin tinzaparin daily for 6 months compared with warfarin did not significantly reduce recurrent VTE and was not associated with reductions in overall death or major bleeding, but was associated with a lower rate of clinically relevant nonmajor bleeding, according to a study in the August 18 issue of JAMA.

Venous thromboembolism is a major cause of illness and death in patients with cancer. Treatment with low-molecular-weight heparin is effective and is recommended over warfarin by clinical practice guidelines. These recommendations are largely based on results from a single, large randomized trial with supportive evidence from additional smaller studies that were conducted over a decade ago in academic centers primarily in North America and Western Europe, according to background information in the article.

Agnes Y. Y. Lee, M.D., M.Sc., of the University of British Columbia, Vancouver, and colleagues randomly assigned 900 adult patients with active cancer and documented deep vein thrombosis or pulmonary embolism to tinzaparin once daily for 6 months vs conventional therapy with tinzaparin once daily for 5 to 10 days followed by warfarin at a dose adjusted to maintain the international normalized ratio (INR) within the therapeutic range for 6 months. The patients, enrolled in 164 centers in Asia, Africa, Europe, and North, Central, and South America between August 2010 and November 2013, were followed up for 180 days and for 30 days after the last study medication dose for collection of safety data.

Recurrent VTE occurred in 31 of 449 patients treated with tinzaparin and 45 of 451 patients treated with warfarin (6-month cumulative incidence, 7.2 percent for tinzaparin vs 10.5 percent for warfarin). There were no differences in major bleeding (12 patients for tinzaparin vs 11 patients for warfarin) or overall mortality (150 patients for tinzaparin vs 138 patients for warfarin).

Tinzaparin significantly reduced the risk of clinically relevant nonmajor bleeding (included bleeding that required any medical or surgical intervention but was not fatal; did not occur in a critical area or organ; or did not cause a fall in hemoglobin of greater than 2 g/dL or lead to a transfusion of 2 or more units of whole blood or red cells) compared with warfarin (49 of 449 patients for tinzaparin vs 69 of 451 patients for warfarin). “Together with the adverse events data, [this trial] demonstrated that tinzaparin, even when given at a full therapeutic dose for up to 6 months, is safe in a broad oncology population,” the authors write.

“Further studies are needed to assess whether the efficacy outcomes would be different in patients at higher risk of recurrent VTE.”

(doi:10.1001/jama.2015.9243; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The study was sponsored and funded by LEO Pharma and had research support from the Sondra and Stephen Hardis Endowed Chair in Oncology Research and the Scott Hamilton CARES Initiative. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, AUGUST 11, 2015

Media Advisory: To contact Rachel E. Patzer, Ph.D., M.P.H., call Holly Korschun at 404-727-3990 or email Hkorsch@emory.edu. To contact editorial co-author Dorry L. Segev, M.D., Ph.D., email Ekaterina Pesheva at epeshev1@jhmi.edu.

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Only about one in four patients with end-stage renal disease in Georgia were referred for kidney transplant evaluation within 1 year of starting dialysis between 2005 and 2011, although there was substantial variability in referral among dialysis facilities, according to a study in the August 11 issue of JAMA.

For most of the more than 600,000 patients in the United States with end-stage renal disease (ESRD), kidney transplantation represents the optimal treatment, providing longer survival, better quality of life, and substantial cost savings compared with dialysis. Dialysis facilities in the United States are required to educate patients with ESRD about all treatment options, including kidney transplantation. Patients receiving dialysis typically require a referral for kidney transplant evaluation at a transplant center to begin the transplantation process, but the proportion of dialysis patients referred for transplantation has been unknown, according to background information in the article.

Rachel E. Patzer, Ph.D., M.P.H., of the Emory University School of Medicine, Atlanta, and colleagues examined variation in dialysis facility-level referral for kidney transplant evaluation and factors associated with referral among patients initiating dialysis in Georgia, the U.S. state with the lowest kidney transplantation rates. The study included data from the United States Renal Data System for 15,279 adult (18-69 years) patients with ESRD from 308 Georgia dialysis facilities from January 2005 to September 2011, followed up through September 2012, and linked to kidney transplant referral data collected from adult transplant centers in Georgia in the same period.

The median within-facility percentage of patients referred within 1 year of starting dialysis at 308 Georgia dialysis facilities was 24 percent. There were 15 facilities (5 percent) that referred zero patients within 1 year of starting dialysis; the maximum referral in a year was 75 percent. Facilities in the lowest tertile of referral (<19 percent) were more likely to treat patients living in high-poverty neighborhoods, had a higher patient to social worker ratio, and were more likely nonprofit compared with facilities in the highest tertile of referral (>31 percent).

Factors associated with lower referral for transplantation, such as white race, older age, and nonprofit facility status, were not necessarily the same as those associated with lower waitlisting, the researchers write. “Results of this study suggest that referral for transplantation among Georgia dialysis facilities is not uniform and that national surveillance data measuring waitlisting and transplantation, but not referral, may be inadequate to assess and intervene on disparities in access to kidney transplantation.”

“These findings may have implications for health policy makers, researchers, clinicians, and patients. Low facility-level referral for transplantation, as well as the variability in referral across Georgia facilities, suggests that standardized guidelines are needed for the content and duration of a patient-clinician educational discussion regarding treatment options at start of dialysis. Socioeconomic status factors were significant barriers to both referral and waitlisting in this study; national policies, such as Medicaid expansion, could help to alleviate disparities,” the authors write.

“Researchers should continue to develop, test, and implement pragmatic interventions to improve knowledge of transplantation among both clinicians and patients. In Georgia, such interventions could focus on those dialysis facilities with the lowest proportions of patients with ESRD referred for kidney transplantation.”

(doi:10.1001/jama.2015.8897; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This work was supported by a National Institute on Minority Health and Health Disparities grant. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Editorial: Improving Access to Kidney Transplantation

“In summary, this important report by Patzer et al has established that major barriers in access to transplantation exist even after a patient has been referred to a transplant center, with 80 percent of referred patients not joining the transplant waitlist within 1 year of referral,” writes Dorry L. Segev, M.D., Ph.D., and colleagues with the Johns Hopkins University School of Medicine, Baltimore, in an accompanying editorial.

“Furthermore, the initial rates of referral were likely low and varied widely between dialysis centers, suggesting that some facilities may have been underreferring patients. Future research to better understand and target post-referral barriers, as well as interventions to identify and improve referral rates in the context of comprehensive transplant education, will be crucial for improving access to kidney transplantation for patients with ESRD.”

(doi:10.1001/jama.2015.8932; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The authors are supported, in part, by grants from the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health. All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, AUGUST 11, 2015

Media Advisory: To contact Shalender Bhasin, M.B.B.S., call Haley Bridger at 617-525-6383 or email hbridger@partners.org.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.8881

Among older men with low testosterone levels, testosterone administration for 3 years compared with placebo did not result in a significant difference in the rates of change in atherosclerosis (thickening and hardening of artery walls), nor was it associated with improved overall sexual function or health-related quality of life, according to a study in the August 11 issue of JAMA. The authors note that because this trial was only powered to evaluate atherosclerosis progression and not cardiovascular events, these findings should not be interpreted as establishing cardiovascular safety of testosterone use in older men such as those enrolled in this trial.

Testosterone sales have increased substantially, particularly among older men, during the past decade. However, the benefits and risks of long-term testosterone administration to older men with age-related decline in testosterone levels remain poorly understood. Although some studies have reported an association of low testosterone levels with increased risk of diabetes, metabolic syndrome, cardiovascular disease (CVD), and mortality, other studies have not shown a consistent association between testosterone levels and incident CVD. The long-term consequences of testosterone supplementation on atherosclerosis in older men remain unknown, according to background information in the article.

Shalender Bhasin, M.B.B.S., of Brigham and Women’s Hospital, Harvard Medical School, Boston, and colleagues randomly assigned 308 men 60 years or older with low or low-normal testosterone levels to receive 7.5 g of 1 percent testosterone (n = 156) or placebo (n = 152) gel packets daily for 3 years. The dose was adjusted to achieve testosterone levels between 500 and 900 ng/dL. Characteristics were similar between groups at study entry: patients were an average age of 68 years; 42 percent had hypertension; 15 percent, diabetes; 15 percent, cardiovascular disease; and 27 percent, obesity.

The researchers found that the rates of subclinical atherosclerosis progression, as measured by changes in common carotid artery intima-media thickness or coronary artery calcium, did not differ significantly between men assigned to the testosterone or placebo groups. Changes in intima-media thickness or calcium scores were not associated with change in testosterone levels among individuals assigned to receive testosterone.

Sexual desire, erectile function, overall sexual function scores, partner intimacy, and health-related quality of life did not differ significantly between groups. Hematocrit (a measure of red blood cells) and prostate-specific antigen levels increased more in testosterone group.

The authors write that this trial was not designed to determine the effects of testosterone on CVD events, and that a substantially larger trial would be needed to determine this.

(doi:10.1001/jama.2015.8881; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, AUGUST 11, 2015

Media Advisory: To contact Joseph S. Ross, M.D., M.H.S., call Ziba Kashef at 203-436-9317 or email Ziba.kashef@yale.edu.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.8761

Of high-risk therapeutic devices approved via the Food and Drug Administration (FDA) Premarket Approval (PMA) pathway between 2010 and 2011, there has been wide variation in both the number and quality of premarket and postmarket studies, with approximately 13 percent of initiated postmarket studies completed between 3 and 5 years after FDA approval, according to a study in the August 11 issue of JAMA.

In the United States, the FDA predominantly grants marketing approval through the PMA pathway for high-risk medical devices, which are defined as those that support or sustain human life, prevent illness, or present potential, unreasonable risk to patients. The PMA pathway requires premarket clinical evidence providing reasonable assurance of device safety and effectiveness and permits supplemental applications whenever postapproval changes are made to the device. Recently, concerns have been raised that the clinical studies supporting FDA approval of these devices lack adequate rigor and are prone to bias, according to background information in the article.

Joseph S. Ross, M.D., M.H.S., of the Yale University School of Medicine, New Haven, Conn., and colleagues examined the clinical evidence generated for high-risk therapeutic devices over the total product life cycle (premarket and postmarket). The analysis included all clinical studies of high-risk therapeutic devices receiving initial market approval via the PMA pathway in 2010 and 2011 identified through ClinicalTrials.gov and publicly available FDA documents as of October 2014. Studies were characterized by type (pivotal, studies that served as the basis of FDA approval; FDA-required postapproval studies [PAS]; or manufacturer/investigator-initiated); premarket or postmarket; status (completed, ongoing, or terminated/unknown); and design features, including enrollment, comparator, and longest duration of primary effectiveness end point follow-up.

In 2010 and 2011, 28 high-risk therapeutic devices received initial marketing approval via the PMA pathway. The researchers identified 286 clinical studies of these devices: 82 (29 percent) premarket and 204 (71 percent) postmarket, among which 18 percent were nonpivotal premarket studies, 10.5 percent pivotal premarket studies, 11.5 percent FDA-required PAS, and 60 percent manufacturer/investigator-initiated postmarket studies. Six of 33 (18 percent) PAS and 12 percent of manufacturer/investigator-initiated postmarket studies were reported as completed. No postmarket studies were identified for 18 percent of devices; 3 or fewer were identified for 46 percent of devices overall.

Premarket clinical studies of high-risk therapeutic devices were limited in number and quality. Nearly all devices were cleared on the basis of 2 studies: 1 nonpivotal and 1 pivotal study.

Approximately half of all studies used no comparator. Median duration of primary effectiveness end point follow-up was 3 months, 9 months, and 12 months for pivotal, completed postmarket, and ongoing postmarket studies, respectively.

“Our characterization of the clinical studies examining high-risk therapeutic medical devices initially approved via the FDA PMA pathway between 2010 and 2011 demonstrates that the amount and quality of evidence generated over the total product life cycle varies widely. Some devices are currently being evaluated through ongoing studies that, if completed, will provide evidence on clinical outcomes for large numbers of patients with planned follow-up of a year or longer. However, most devices have been or will be evaluated through only a few studies, which often focus on surrogate markers of disease in small numbers of patients followed up over short periods of time and study indications that differ from the original FDA-approved indication,” the authors write.

(doi:10.1001/jama.2015.8761; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, AUGUST 11, 2015

Media Advisory: To contact Vitaly A. Kushnir, M.D., email Mat Probasco at mprobasco@thechr.com.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.7556

Compared to using fresh oocytes (eggs) for in vitro fertilization, use of cryopreserved (frozen) donor oocytes in 2013 was associated with lower live birth rates, according to a study in the August 11 issue of JAMA.

Use of oocytes donated for in vitro fertilization (IVF) has increased in recent years. Donated fresh oocytes traditionally have been used immediately, creating embryos for transfer into the uterus, with extra embryos being cryopreserved for later use. In January 2013, the American Society for Reproductive Medicine declared the technique of oocyte cryopreservation (egg freezing) no longer experimental, although it called for “more widespread clinic-specific data on the safety and efficacy of oocyte cryopreservation … before universal donor oocyte banking can be recommended.” Based on data that IVF outcomes with cryopreserved and fresh donor oocytes are comparable, some IVF centers established frozen donor egg banks. However, data reflecting IVF outcomes in routine clinical practice with cryopreserved donor oocytes have not previously been published, according to background information in the article.

Vitaly A. Kushnir, M.D., of the Center for Human Reproduction, New York, and colleagues used data from the 2013 annual report of U.S. IVF center outcomes published by the Society for Assisted Reproductive Technology to compare live birth and cycle cancellation (started IVF cycles which do not reach egg retrieval and/or embryo transfer) rates using either fresh or cryopreserved donor oocytes. This data set is based on center-specific voluntarily reported outcomes from 380 of 467 (81 percent) U.S.­ based fertility centers, which in 2013 collectively performed 92 percent of all IVF cycles.

Of 11,148 oocyte donation cycles, 2,227 (20 percent) involved use of cryopreserved donor oocytes. Initiated cycles were canceled in 12 percent of fresh oocyte cycles vs 8.5 percent of cryopreserved oocyte cycles. Per started recipient cycle, the live birth rates were 50 percent with fresh vs 43 percent with cryopreserved oocytes. Per embryo transfer, the live birth rates were 56 percent with fresh vs 47 percent with cryopreserved oocytes.

The authors write that the reasons for lower live birth rates with use of cryopreserved oocytes remain to be established. “One possible explanation is less opportunity for proper embryo selection due to smaller starting numbers of oocytes, leading to fewer embryos available for transfer. Alternatively, oocyte quality may be negatively affected by cryopreservation and thawing.” They add that the added convenience and lower cycle costs with use of cryopreserved oocytes must be balanced against the lower live birth rates.

The researchers note that these findings need to be viewed with caution because they are based on anonymized aggregate outcomes, which do not allow adjustments for confounding patient characteristics, such as donor and recipient ages, infertility diagnosis, and embryo stage.

(doi:10.1001/jama.2015.7556; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, AUGUST 11, 2015

Media Advisory: To contact Christian F. Poets, M.D., email christian-f.poets@med.uni-tuebingen.de. To contact editorial author Lex W. Doyle, M.D., email lwd@unimelb.edu.au.

To place an electronic embedded link to this study and editorial in your story This link to the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.8841 This will be the link to the editorial: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.9136

Among extremely preterm infants, prolonged episodes of hypoxemia (abnormally low levels of oxygen in the blood, which leads to shortness of breath) during the first 2 to 3 months after birth were associated with an increased risk of disability or death at 18 months, according to a study in the August 11 issue of JAMA.

Almost all extremely preterm infants (those born at < 28 weeks’ gestation) experience intermittent hypoxemia and bradycardia (a slow heart rate) during their stay in the neonatal intensive care unit. The relationship between neonatal hypoxemia or bradycardia and later neurodevelopment in this population of high-risk preterm infants is uncertain, according to background information in the article.

Christian F. Poets, M.D., of Tuebingen University Hospital, Tuebingen, Germany, and colleagues examined the association between intermittent hypoxemia or bradycardia and death or disability. The study included 1,019 infants with gestational ages of 23 weeks 0 days through 27 weeks 6 days who were born between December 2006 and August 2010 and survived to a postmenstrual age of 36 weeks. Follow-up assessments occurred between October 2008 and August 2012. The researchers used data from infants who were part of the Canadian Oxygen Trial (25 hospitals in Canada, the United States, Argentina, Finland, Germany, and Israel).

Average percentages of recorded time with hypoxemia for the least and most affected 10 percent of infants were 0.4 percent and 13.5 percent, respectively. Corresponding values for bradycardia were 0.1 percent and 0.3 percent. The primary outcome (a composite of death after 36 weeks’ postmenstrual age, motor impairment, cognitive or language delay, severe hearing loss, or blindness at 18 months) was ascertained for 972 infants and present in 414 (43 percent). Hypoxemic episodes were associated with an estimated increased risk of late death or disability at 18 months of 56.5 percent in the highest decile (one of 10 groups) of hypoxemic exposure vs 37 percent in the lowest decile. This association was significant only for prolonged hypoxemic episodes lasting at least 1 minute.

Relative risks for all secondary outcomes (motor impairment, cognitive or language delay, and severe retinopathy of prematurity [a disorder of the retina]) were similarly increased after prolonged hypoxemia.

“If these observations are confirmed in future studies, further research on the prevention of such episodes will be needed,” the authors write.

The researchers note that intermittent bradycardia did not significantly add to the risk of adverse outcomes, suggesting that bradycardia in the absence of concurrent hypoxemia may not be of prognostic importance. In addition, the severity of intermittent hypoxemia added little prognostic value to the simpler measure of the percentage of time spent with hypoxemia.

The authors add that should the observation be confirmed in future research that episodes of hypoxemia lasting less than 1 minute are not associated with adverse outcomes in extremely preterm infants, this would be important information for both clinicians and parents.

(doi:10.1001/jama.2015.8841; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was funded exclusively by a Canadian Institutes of Health Research grant. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Editorial: Hypoxemic Episodes and Adverse Neurodevelopmental Outcome in Extremely Preterm Infants

“If hypoxemia is proven to cause adverse neurodevelopment, any future interventions to reduce prolonged hypoxemic episodes, such as doxapram [a respiratory stimulant] or higher doses of caffeine, as suggested by Poets et al, must be evaluated in rigorous randomized clinical trials to minimize exposure to therapies that are useless or even harmful,” writes Lex W. Doyle, M.D., of the University of Melbourne, Parkville, Victoria, Australia, in an accompanying editorial.

“Such trials should have long-term developmental outcome as the primary end point, rather than short-term end points, such as a reduction in the number or duration of hypoxemic episodes. Neonatal intensive care is littered with examples of treatments that were introduced based on observational data or even no data, only to be proven to be disastrous when tested properly in randomized clinical trials. In the meantime, other treatments known from randomized clinical trials to improve long-term neurodevelopmental outcome for extremely preterm infants, such as magnesium sulfate before birth, regular doses of caffeine, or developmental care interventions after discharge, should be maximized.”

(doi:10.1001/jama.2015.9136; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, AUGUST 4, 2015

Media Advisory: To contact Melissa A. Polusny, Ph.D., call Ralph Heussner at 612-467-3012 or email Ralph.heussner@va.gov. To contact editorial co-author David J. Kearney, M.D., call Chad Hutson at 206-764-2589 or email Chad.Hutson@va.gov.

To place an electronic embedded link to this study and editorial in your story This link to the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.8361 This will be the link to the editorial: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.7522

In a randomized trial that included veterans with posttraumatic stress disorder (PTSD), those who received mindfulness-based stress reduction therapy showed greater improvement in self-reported PTSD symptom severity, although the average improvement appears to have been modest, according to a study in the August 4 issue of JAMA, a violence/human rights theme issue.

Posttraumatic stress disorder affects 23 percent of veterans returning from Afghanistan and Iraq. Left untreated, PTSD is associated with high rates of other disorders, disability, and poor quality of life. Evidence suggests that mindfulness-based stress reduction, an intervention that teaches individuals to attend to the present moment in a nonjudgmental, accepting manner, can result in reduced symptoms of depression and anxiety. By encouraging acceptance of thoughts, feelings, and experiences without avoidance, mindfulness-based interventions target experiential avoidance, a key factor in the development and maintenance of PTSD, and may be an acceptable type of intervention for veterans who have poor adherence to existing treatments for PTSD, according to background information in the article.

Melissa A. Polusny, Ph.D., of the Minneapolis Veterans Affairs Health Care System, and colleagues randomly assigned 116 veterans with PTSD to receive nine sessions of mindfulness-based stress reduction therapy (n = 58) or present-centered group therapy (n = 58), an active-control condition consisting of nine weekly group sessions focused on current life problems. Outcomes were assessed before, during, and after treatment and at 2-month follow-up.

Participants in the mindfulness-based stress reduction group demonstrated greater improvement in self-reported PTSD symptom severity during treatment and at 2-month follow-up. Although participants in the mindfulness-based stress reduction group were more likely to show clinically significant improvement in self-reported PTSD symptom severity (49 percent vs 28 percent with present-centered group therapy) at 2-month follow-up, there was no difference in rates of loss of PTSD diagnosis at posttreatment (42 percent vs 44 percent) or at 2-month follow-up (53 percent vs 47 percent).

“Findings from the present study provide support for the efficacy of mindfulness-based stress reduction for the treatment of PTSD among veterans,” the researchers write. “However, the magnitude of the average improvement suggests a modest effect.”

(doi:10.1001/jama.2015.8361; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This material is the result of work supported with resources and the use of facilities at the Minneapolis VA Health Care System. This research was supported by a VA grant to Dr. Lim. All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Editorial: Broadening the Approach to Posttraumatic Stress Disorder and the Consequences of Trauma

David J. Kearney, M.D., and Tracy L. Simpson, Ph.D., of the VA Puget Sound Health Care System, Seattle, comment on the findings of this study in an accompanying editorial.

“The rate of clinically significant PTSD symptom reduction of 49 percent for those randomized to mindfulness-based stress reduction (MBSR) is similar to that reported for empirically supported treatment approaches to PTSD … and consistent with the rate of clinically significant improvement in PTSD symptoms of 48 percent found in a before-and-after study of MBSR among veterans. Although the results reported by Polusny et al are promising, the short duration of follow-up calls into question whether the effects of MBSR persist over time; thus, additional studies of MBSR and other mindfulness-based interventions for PTSD are warranted.”

(doi:10.1001/jama.2015.7522; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This material is based on work supported by the U.S. Department of Veterans Affairs Office of Research and Development. The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, AUGUST 4, 2015

Media Advisory: To contact Steven A. Sumner, M.D., M.Sc., call Courtney Lenard at 404-639-3286 or email clenard@cdc.gov.

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Even though homicide and assault rates have decreased in the U.S. in recent years, the number of these and other types of violent acts remains high, according to a report in the August 4 issue of JAMA, a violence/human rights theme issue. The authors write that multiple strategies exist to improve interpersonal violence prevention efforts, and health care providers are an important part of this solution.

Interpersonal violence is a pervasive public health, social, and developmental threat that affects millions of U.S. residents each year. It is a leading cause of death in the U.S., particularly among children, adolescents and young adults. Exposure to violence can cause immediate physical wounds that clinicians recognize and treat but can also result in long-lasting mental and physical health conditions that are often less apparent to health care providers. Surveillance systems, programs, and policies to address violence often lack broad, cross-sector collaboration, and there is limited awareness of effective strategies to prevent violence, according to background information in the article.

Steven A. Sumner, M.D., M.Sc., of the Centers for Disease Control and Prevention, Atlanta, and colleagues examined the burden of interpersonal violence in the United States and challenges to violence prevention efforts and sought to identify prevention opportunities. The researchers reviewed data from various health and law enforcement surveillance systems (listed at the end of this news release).

The researchers found that homicide rates have decreased from a peak of 10.7 per 100,000 persons in 1980 to 5.1 per 100,000 in 2013. Aggravated assault rates have decreased from a peak of 442 per 100,000 in 1992 to 242 per 100,000 in 2012. Despite the decrease in these rates, annually there are more than 16,000 homicides and 1.6 million nonfatal assault injuries requiring treatment in emergency departments. More than 12 million adults experience intimate partner violence annually and more than 10 million children younger than 18 years of age experience some form of maltreatment from a caregiver, ranging from neglect to sexual abuse, but only a small percentage of these violent incidents are reported to law enforcement, health care clinicians, or child protective agencies.

The researchers write that exposure to violence increases vulnerability to a broad range of mental and physical health problems over the life course; for example, meta-analyses indicate that exposure to physical abuse in childhood is associated with a 54 percent increased odds of depressive disorder, a 78 percent increased odds of sexually transmitted illness or risky sexual behavior, and a 32 percent increased odds of obesity.

Rates of violence vary by age, geographic location, sex, and race/ethnicity, and significant disparities exist. Homicide is the leading cause of death for non-Hispanic blacks from age 1 through 44 years, whereas it is the fifth most common cause of death among non-Hispanic whites in this age range. Additionally, efforts to understand, prevent, and respond to interpersonal violence have often neglected the degree to which many forms of violence are interconnected at the individual level, across relationships and communities, and even intergenerationally.

The authors write that the most effective violence prevention strategies include parent and family-focused programs, early childhood education, school-based programs, therapeutic or counseling interventions, and public policy. For example, a systematic review of early childhood home visitation programs found a 39 percent reduction in episodes of child maltreatment in intervention participants compared with control participants.

“The scientific literature indicates quite clearly that preventing interpersonal violence is strategic from a health and public health perspective. It is strategic because of the consistently documented high levels of violence to which young children, adolescents, and young adult women and men are exposed. Furthermore, exposure to violence plays an important role, not just in causing physical injuries and homicide, but also in the etiology of mental illness, chronic disease, and infectious diseases such as HIV. Thus, preventing exposure to violence can have downstream effects on a broad range of health problems.”

“Finally, there is a substantial and rapidly growing evidence base on what works to prevent violence. This evidence suggests that priority should be given to interventions that can affect multiple forms of violence, particularly those that seek to prevent violence among children and youth. The effects of violence and the probability of involvement in future violence are dose dependent; thus, considerable gains can be made by early intervention,” the authors write.

(doi:10.1001/jama.2015.8371; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

For this report, the researchers reviewed data from health and law enforcement surveillance systems including the National Vital Statistics System, the Federal Bureau of Investigation’s Uniform Crime Reports, the U.S. Justice Department’s National Crime Victimization Survey, the National Survey of Children’s Exposure to Violence, the National Child Abuse and Neglect Data System, the National Intimate Partner and Sexual Violence Survey, the Youth Risk Behavior Surveillance System, and the National Electronic Injury Surveillance System-All Injury Program.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, AUGUST 4, 2015

Media Advisory: To contact Karin V. Rhodes, M.D., M.S., call Katie Delach at 215-349-5964 or email katie.delach@uphs.upenn.edu.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.8369

A brief motivational intervention delivered during an emergency department visit did not improve outcomes for women with heavy drinking involved in abusive relationships, according to a study in the August 4 issue of JAMA, a violence/human rights theme issue.

There is a strong and reciprocal association between two highly prevalent public health problems: intimate partner violence (IPV) and heavy drinking. Each risk individually represents major costs to individuals, families, and society. The emergency department (ED) visit is conceptualized as a sensitive period or window of time when exposure to motivational health promotion might have an influence on behaviors. Integrated brief interventions for IPV and heavy drinking have not been tested, according to background information in the article.

Karin V. Rhodes, M.D., M.S., of the University of Pennsylvania, Philadelphia, and colleagues randomly assigned 600 IPV-involved female ED patients who exceeded safe drinking limits to brief intervention (n = 242), assessed control (n = 237), or no-contact control (n = 121). All received social service referrals. The brief intervention was a 20- to 30-minute manual-guided motivational intervention delivered by master’s-level therapists with a follow-up telephone booster. The assessed control group received the same number of assessments as the brief intervention group but no intervention; the no-contact control group was assessed only once at 3 months.

Incidents of heavy drinking and IPV were assessed weekly for 12 weeks using an interactive voice response system. Of 600 participants, 80 percent were black women with an average age of 32 years. Retention among study participants was 89 percent for 2 or more interactive voice response system calls. Seventy-eight percent of women completed the 3-month interview, 79 percent at 6 months, and 71 percent at 12 months.

During the 12-week period following the brief motivational intervention, there were no significant differences between the intervention group and the assessed control group on weekly assessments for experiencing IPV or heavy drinking. From baseline to 12 weeks, the number of women with any IPV in the past week decreased from 57 percent in the intervention group to 43 percent and from 63 percent in the assessed control group to 41 percent (absolute difference of 8 percent; not statistically significant). From baseline to 12 weeks, the number of women with past week heavy drinking decreased from 51 percent in the intervention group to 43 percent and from 46 percent in the assessed control group to 41 percent (absolute difference of 3 percent).

At 12 months, 43 percent of the intervention group and 47 percent of the assessed control group reported no IPV during the previous 3 months and 19 percent of the intervention group and 24 percent of the control group had reduced their alcohol consumption to sex-specific National Institute on Alcohol Abuse and Alcoholism safe drinking levels.

“We did find that over time, reports of experiencing and perpetrating IPV and days of heavy drinking decreased significantly within the intervention and the control groups alike. However, there was no evidence that these outcomes were influenced by the intervention,” the authors write.

The researchers note that integrated interventions that address multiple risk factors in the context of violence exposure may require a more in-depth approach than can be feasibly provided in an ED setting.

“These findings do not support a brief motivational intervention in this setting.”

(doi:10.1001/jama.2015.8369; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This project was funded by an award from the National Institute on Alcohol Abuse and Alcoholism. The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Sommers reported receiving book royalties from FA Davis. No other disclosures were reported.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, AUGUST 4, 2015

Media Advisory: To contact Joanne Klevens, M.D., Ph.D., call Courtney Lenard at 404-639-3286 or email clenard@cdc.gov.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.6755

Screening women for partner violence and providing a resource list did not influence the number of hospitalizations, emergency department, or outpatient care visits compared with women only receiving a resource list or receiving no intervention over 3 years, according to a study in the August 4 issue of JAMA, a violence/human rights theme issue.

The U.S. Preventive Services Task Force recommends women of reproductive age be screened for partner violence. However, others, such as the World Health Organization conclude there is insufficient evidence for this recommendation. Joanne Klevens, M.D., Ph.D., of the U.S. Centers for Disease Control and Prevention, Atlanta, and colleagues had conducted a randomized clinical trial that allocated women seeking care in outpatient clinics to 1 of 3 study groups: computerized partner violence screening and provision of a local resource list, universal provision of a partner violence resource list without screening, or a no screen/no resource list control group. No differences were found in women’s quality of life, days lost from work or housework, use of health care and partner violence services, or the recurrence of partner violence after 1 year.

In this report, the authors examined women’s use of health services over 3 years. Participants’ electronic medical records were searched for outpatient care visits, emergency department visits, and hospitalizations. Of 2,708 women randomized, 8 were unenrolled, leaving 2,700 women with electronic medical records; 15 percent reported partner violence in the year before enrollment. The average age was 39 years; 55 percent of participants were black and 37 percent Latina.

For the full sample, adjusted estimates showed no statistically significant differences between study groups in the average number of hospitalizations (0.2), emergency department visits (0.7), or outpatient care visits (12.2) in the 3 years following enrollment. No differences in these outcomes were found among the subgroup of women who reported experiencing partner violence in the year before enrollment.

“Our data do not support providing a partner violence resource list with or without computerized screening of women in urban health care settings to improve health outcomes,” the authors write.

“The consistency of the results at 1 year and 3 years contributes to greater confidence in the findings. These null findings are consistent with other trials in primary care settings. Research should focus on more intensive interventions among women already identified as abused.”

(doi:10.1001/jama.2015.6755; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was funded by the U.S. Centers for Disease Control and Prevention, National Center for Injury Prevention and Control, Division of Violence Prevention. The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, AUGUST 4, 2015

Media Advisory: To contact Jay G. Silverman, Ph.D., call Heather Buschman at 619-543-6163 or email hbuschman@ucsd.edu.

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More than 1 in 4 female sex workers in the northern Mexico cities of Tijuana and Ciudad Juarez reported entering the sex trade as minors, and entering the sex trade as an adolescent vs as an adult was associated with a greater risk for HIV infection, according to a study in the August 4 issue of JAMA, a violence/human rights theme issue.

Adolescents migrating from Central America and Mexico to the United States are at risk for being trafficked into the sex industry in Mexico’s northern border cities. Research from other regions indicates that those entering the sex trade as adolescents (vs as adults) are more likely to experience sexual violence and to become infected with HIV. Apart from 1 study among injection drug users, no research exists on the prevalence of minors in the sex industry in Latin America or their subsequent risk for violence and HIV infection, according to background information in the article.

Jay G. Silverman, Ph.D., of the University of California–San Diego, La Jolla, Calif., and colleagues studied female sex workers age 18 years or older from Tijuana and Ciudad Juarez. Indoor and street sex work venues were randomly sampled based on mapping of all venues. Confidential computer-assisted surveys were completed to assess prevalence of adolescent (ages 16-17 years) and early adolescent (ages <16 years) entry to the sex trade and associations of age at entry with violence to force commercial sex, high-client volume (>10 clients/day), and no condom use during the initial 30 days after entry.

Of 1,041 individuals screened, 614 were eligible and 603 participated. The average age was 34 years; 25.4 percent reported entering the sex trade before the age of 18 years and 11.8 percent reported entry before the age of 16 years. Compared with those entering sex work as adults, those entering the sex trade as adolescents were more likely to report experiencing violence to force commercial sex (19.7 percent among those aged <16 years vs 8.7 percent among adults), high client volume (21.1 percent for <16 years; 19.5 percent for 16-17 years; 9.6 percent for adults), and never use of condoms with clients (35.2 percent for <16 years vs 8 percent for adults) during their first 30 days in the sex industry. Those reporting entering the sex trade as adolescents were more likely to be infected with HIV compared with those entering as adults (5.9 percent for age <18 years vs 1.6 percent for adults).

“Entering the sex trade as an adolescent vs as an adult was associated with a greater risk for HIV infection, which may relate to elevated risks for violence to force participation in commercial sex, higher numbers of clients, and condom nonuse during initiation to the sex industry. Efforts to effectively protect adolescents vulnerable to sex trade entry and assist adolescents in the sex industry are needed,” the authors write.

(doi:10.1001/jama.2015.7376; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The study was supported via funding from the National Institute on Drug Abuse and the University of California–San Diego AIDS Research Institute via the National Institute of Allergy and Infectious Diseases. The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, JULY 28, 2015

Media Advisory: To contact Harlan M. Krumholz, M.D., S.M., email harlan.krumholz@yale.edu or call Karen Peart at 203-432-1326 or email karen.peart@yale.edu.

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Among Medicare fee-for-service beneficiaries age 65 years or older, all-cause mortality and hospitalization rates, along with inpatient expenditures per beneficiary, decreased from 1999 to 2013, according to a study in the July 28 issue of JAMA, a theme issue on Medicare and Medicaid at 50. There has also been a decrease in recent years in total hospitalizations and inpatient expenditures for the last 6 months of life.

In recent decades, the United States has experienced a period of dynamic change in health care technology, health care delivery, and health behaviors. Given these changes, which could provide benefit or cause unintended harm, there is a need to assess the results that are being achieved. The Medicare fee-for-service program is ideally positioned to provide information on trends in mortality, hospitalizations, and hospitalization outcomes during this period in health care. A comprehensive analysis of national hospital trends in the Medicare fee-for-service population can provide an assessment of past performance and targets for future interventions, according to background information in the article.

Harlan M. Krumholz, M.D., S.M., of the Yale University School of Medicine, New Haven, Conn., and colleagues examined national trends between 1999 and 2013 in all-cause mortality for all Medicare beneficiaries and trends in all-cause hospitalization and hospitalization-associated outcomes and expenditures for fee-for-service beneficiaries. The analyses included adults 65 years of age or older. Geographic variation, stratified by key demographic groups, and changes in the intensity of care for fee-for-service beneficiaries in the last 1, 3, and 6 months of life were also assessed.

The sample consisted of 68,374,904 Medicare beneficiaries (fee-for-service and Medicare Advantage). The annual all-cause mortality rate across the Medicare population declined from 5.3 percent in 1999 to 4.5 percent in 2013. Among hospitalized fee-for-service beneficiaries, in-hospital mortality declined, as did 30-day and 1-year mortality.

Among fee-for-service beneficiaries (n = 60,056,069), the total number of hospitalizations decreased between 1999 and 2013, as did the number of hospitalizations that involved major surgical procedures. The median hospital length of stay for beneficiaries who had at least 1 hospitalization declined from 5 to 4 days. Average inflation-adjusted inpatient expenditures per Medicare fee-for-service beneficiary declined from $3,290 to $2,801.

Among fee-for-service beneficiaries in the last 6 months of life, the number of hospitalizations decreased from 131 to 103 per 100 deaths. The percentage of beneficiaries with 1 or more hospitalizations decreased from 70.5 to 57 per 100 deaths, while the inflation-adjusted inpatient expenditure per death increased from $15,312 in 1999 to $17,423 in 2009 and then decreased to $13,388 in 2013. Findings were consistent across geographic and demographic groups.

The researchers also found that patients were increasingly discharged to rehabilitation and nursing facilities or with home health care, whereas the proportion of patients discharged to home without care decreased steadily.

“Even though it is difficult to disentangle the specific reasons for improvement, it is clear that over the past 15 years there have been marked reductions in mortality, hospitalization, and adverse hospital outcomes among the Medicare population aged 65 years or older,” the authors write.

(doi:10.1001/jama.2015.8035; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Dr. Krumholz is supported by a grant from the National Heart, Lung, and Blood Institute. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Please Note: For this study, there will be multimedia content available, including the JAMA Report video, embedded and downloadable video, audio files, text, documents, and related links. This content will be available at the embargo time at http://broadcast.jamanetwork.com/.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, JULY 28, 2015

Media Advisory: To contact Benjamin D. Sommers, M.D., Ph.D., call Veronica Jackson at 202-690-5488 or email veronica.jackson@hhs.gov.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.8421

Results of a national survey that included more than half a million adults indicates significant improvements in trends for self-reported insurance coverage, access to a personal physician and medications, affordability and health after the Affordable Care Act’s (ACA’s) first and second open enrollment periods, according to a study in the July 28 issue of JAMA, a theme issue on Medicare and Medicaid at 50. Analyses also demonstrated that the largest improvements in coverage and access to medicine occurred among racial/ethnic minorities, suggesting that the ACA may be associated with reductions in long-standing disparities in access to care.

The ACA’s Medicaid expansion and new subsidized private coverage from insurance marketplaces have entered their second year. The law’s first 2 open enrollment periods are complete, the most recent finishing February 15, 2015. How coverage expansion is affecting access to care and health remains an important question, according to background information in the article.

Benjamin D. Sommers, M.D., Ph.D., of the Harvard T. H. Chan School of Public Health and Brigham and Women’s Hospital, Boston, and U.S. Department of Health and Human Services, Washington, D.C., and colleagues analyzed results of the 2012-2015 Gallup-Healthways Well-Being Index, a daily national telephone survey. Using methods to adjust for pre-ACA trends and sociodemographics, the researchers examined changes in outcomes for the U.S. adult population age 18 through 64 years (n = 507,055) since the first open enrollment period began in October 2013. Pre-ACA (January 2012-September 2013) and post-ACA (January 2014-March 2015) changes for adults with incomes below 138 percent of the poverty level in Medicaid expansion states (n = 48,905 among 28 states and Washington, D.C.) vs nonexpansion states (n = 37,283 among 22 states) were compared.

Among the 507,055 adults in the survey, pre-ACA trends were significantly worsening for all outcomes. Compared with the pre-ACA trends, by the first quarter of 2015, the adjusted proportions who were uninsured decreased by 7.9 percentage points; who lacked a personal physician, -3.5 percentage points; who lacked easy access to medicine, -2.4 percentage points; who were unable to afford care, -5.5 percentage points; who reported fair/poor health, -3.4 percentage points; and the percentage of days with activities limited by health, -1.7 percentage points.

Coverage changes were largest among minorities; for example, the decrease in the uninsured rate was larger among Latino adults (-11.9 percentage points) than white adults (-6.1 percentage points). Medicaid expansion was associated with significant reductions among low-income adults in the uninsured rate, lacking a personal physician, and difficulty accessing medicine. “As states continue to debate whether to expand Medicaid under the ACA, these results add to the growing body of research indicating that such expansions are associated with significant benefits for low-income populations,” the authors write.

The researchers add that from a clinical perspective, positive trends were detected for self-reported health and functional status among individuals with chronic medical conditions, who may potentially benefit most from expanded coverage. “These results might reflect changes in the management of chronic conditions, peace of mind from gaining insurance, or factors unrelated to the ACA.”

The authors note that whether the changes found in this study are related directly to the ACA’s coverage expansions is not possible to determine with this type of study design. “For instance, the economic recovery may have also influenced the study outcomes, though the analysis did adjust for several potential confounders including income, individual employment, and state unemployment rates.”

(doi:10.1001/jama.2015.8421; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This research was supported by the authors’ employment at the U.S. Department of Health and Human Services and did not receive any external grants or corporate funding. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, JULY 28, 2015

Media Advisory: To contact Karl Y. Bilimoria, M.D., M.S., email Bret Coons at bcoons@nm.org.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.8609

Hospitals that were penalized more frequently in the Hospital-Acquired Condition (HAC) Reduction Program offered advanced services, were major teaching institutions and had better performance on other publicly reported process-of-care and outcome measures, according to a study in the July 28 issue of JAMA, a theme issue on Medicare and Medicaid at 50. These findings suggest that penalization in this program may not reflect poor quality of care but rather may be due to measurement and validity issues of the HAC program component measures.

The Affordable Care Act (ACA) established the HAC program in an effort to reduce the incidence of preventable adverse events that occur during hospitalizations in the United States. This program reduces payments to the lowest-performing hospitals. However, it is uncertain whether the program accurately measures quality and fairly penalizes hospitals, according to background information in the article.

Karl Y. Bilimoria, M.D., M.S., of the Feinberg School of Medicine, Northwestern University, Chicago, and colleagues evaluated the characteristics and performance of hospitals penalized in the HAC Reduction Program. Data for hospitals participating in this program for FY2015 were obtained from CMS’ Hospital Compare and combined with the 2014 American Hospital Association Annual Survey and FY2015 Medicare Impact File. The authors examined the association between hospital characteristics and HAC program penalization.

An 8-point hospital quality summary score was created using hospital characteristics related to clinical volume, accreditations, and offering of advanced care services. Publicly reported process-of-care and outcome measures were examined from 4 clinical areas (surgery, acute heart attack, heart failure, pneumonia).

Of the 3,284 hospitals participating in the HAC program, 721 (22 percent) were penalized. Hospitals were more likely to be penalized if they were accredited by the Joint Commission (24 percent accredited, 14 percent not accredited); they were major teaching hospitals (42 percent) or very major teaching hospitals (62 percent vs nonteaching hospitals, 17 percent); they cared for more complex patient populations based on case mix index; or they were safety-net hospitals vs non-safety-net hospitals (28 percent vs 20 percent).

Hospitals with higher quality summary scores had significantly better performance on 9 of 10 publicly reported process and outcomes measures compared with hospitals that had lower quality scores. However, hospitals with the highest quality score of 8 were penalized significantly more frequently than hospitals with the lowest quality score of 0 (67 percent [37/55] vs 13 percent [53/422]).

The researchers speculate that one explanation for these findings may be that these component measures are affected by surveillance bias, where differences in clinical practice result in varying rates of identifying an adverse outcome. “Hospitals that look more for adverse events frequently identify more events and incorrectly appear to have worse performance.”

In addition, hospital-to-hospital differences in information technology may also result in differences in the detection of adverse events.

The authors conclude that “these paradoxical findings suggest that the approach for assessing hospital penalties in the HAC Reduction Program merits reconsideration to ensure it is achieving the intended goals.”

(doi:10.1001/jama.2015.8609; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, JULY 28, 2015

Media Advisory: To contact Drew Altman, Ph.D., call Amy Jeter at 650-854-9400 or email amyj@kff.org.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.7811

Although Medicare and Medicaid are playing a role in health care payment and delivery reform innovation, it will be difficult to enact large-scale program changes because of the conflicting priorities of beneficiaries, health practitioners and organizations, and policy makers, according to an article in the July 28 issue of JAMA, a theme issue on Medicare and Medicaid at 50.

Medicare and Medicaid are the nation’s two largest public health insurance programs, serving the elderly, those with disabilities, and mostly lower-income populations. Drew Altman, Ph.D., of the Kaiser Family Foundation, Menlo Park, Calif., and William H. Frist, M.D., former U.S. Senate majority leader, analyzed the roles of Medicare and Medicaid in the health system using publicly available data and private surveys of the public and beneficiaries.

Together, Medicare (n = 55 million) and Medicaid (n = 66 million) provide health coverage to about 111 million people, or 1 in 3 Americans, including 10 million dual-eligible people covered by both programs. That number is projected to reach 139 million people by 2025. The programs accounted for approximately $1 trillion in total spending in 2013 (Medicare, $585.7 billion; Medicaid, $449.4 billion). Together, they constitute 39 percent of national health spending, account for 23 percent of the federal budget, and generate 43 percent of hospital revenues.

Spending on the two programs for 2013 to 2023 is projected to increase at an average rate of 3.7 percent per year, which is slower than the projected growth for private health insurance, despite that Medicare and Medicaid generally serve populations with more illness and health problems.

The authors note that future issues confronting both programs include whether they will remain open-ended entitlements, the degree to which the programs may be privatized, the scope of their cost-sharing structures for beneficiaries, and the roles the programs will play in payment and delivery reform.

“While public attention has focused on the Affordable Care Act (ACA), Medicare and Medicaid remain the core of the nation’s public health insurance system. Together these programs serve more than a hundred million of the nation’s most vulnerable people—low-income children and adults, people with disabilities, and older persons. Because beneficiaries, health practitioners and organizations, and policy makers all have different interests in these programs, it is difficult to reconcile their conflicting perspectives and priorities and enact large-scale program changes. Few policies can simultaneously constrain spending, improve reimbursement rates, and protect and strengthen benefits. Reaching bipartisan agreement on policy change is especially challenging in the current polarized political environment.”

The authors add that both Medicare and Medicaid are changing their roles in the health care system to become more proactive forces for payment and delivery reform. “The goal of moving 90 percent of traditional Medicare reimbursements to alternative value-based payment arrangements by 2016 signals a new effort to use Medicare’s purchasing power to promote quality and reform the delivery of care. While it gets less attention, payment and delivery reform in Medicaid is also under way in virtually every state. Medicaid programs have also been increasingly aggressive purchasers of drugs.”

Together, Medicare and Medicaid have more than $1 trillion a year in purchasing power, “and they are now pursuing common strategies in the form of accountable care organizations, medical homes, managed care for chronically ill persons, and a variety of value-based payment options.”

“The private sector is generally regarded as the engine of innovation in the United States, but on the 50th anniversary of Medicare and Medicaid, health care’s 2 largest public health insurance programs are playing a much larger role in innovation in payment and delivery reform and reshaping the delivery of care for the future.”

(doi:10.1001/jama.2015.7811; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including financial disclosures, funding and support, etc.

Please Note: A podcast interview on this report will be available at JAMA.com at the embargo time.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, JULY 28, 2015

Media Advisory: To contact Sonja M. Swenson, B.A., call Adam Gorlick at 650-724-9842 or email agorlick@stanford.edu.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.7169

In an analysis of expenditures for outpatient pharmacy products used by publicly insured children with serious chronic illness in California, treating hemophilia accounted for about 40 percent of expenditures but included just 0.4 percent of the group studied, suggesting a need to improve pricing for this and other effective yet high-cost medications, according to a study in the July 28 issue of JAMA.

Children with serious chronic conditions are increasingly likely to survive infancy, intensifying demands on health care delivery. Medication is one driver of their health care costs; high-cost drugs threaten cost-containment efforts. Sonja M. Swenson, B.A., of Stanford University, Stanford, Calif., and colleagues analyzed paid claims for children (ages, 0-21 years) using the California Children’s Services (CCS) paid claims data set (2010-2012). CCS provides insurance coverage, care coordination, and a regionalized system of pediatric specialty care facilities for approximately 180,000 publicly insured children with serious chronic illness. The data set includes age, sex, race/ethnicity, county of residence, enrollment dates, primary and secondary eligible diagnoses, claim diagnoses, and procedures for every enrollee. This study included children enrolled through fee-for-service care for at least 6 continuous months.

The analysis examined records of 34,330 children. Outpatient pharmacy expenditures totaled $475,718,130 (20 percent of total health care expenditures); per-child pharmacy expenditures ranged from $0.16 to $56,849,034, and average and median per-child expenditures were $13,857 and $791, respectively.

The product class of blood formation, coagulation, and thrombosis agents accounted for the greatest share (42 percent) of outpatient pharmacy expenditures, and antihemophilic factor (a protein that is essential to normal blood clotting and is lacking or deficient in persons having hemophilia A) represented 98 percent of this class’s expenditures or 41 percent of total pharmacy expenditures. Children with an antihemophilic factor paid claim were 0.4 percent of the cohort. The average per-child expenditure for antihemophilic factor was $1,343,262. Among children with antihemophilic factor claims and enrolled for all 3 years, the average and median per-child annualized expenditures were $634,054 and $152,280, respectively. The next largest percentage of total pharmacy expenditures was 9.2 percent for central nervous system agents, with an average expenditure of $1,869 per child.

“Antihemophilic factor is highly efficacious and essential in caring for children with hemophilia, putting pressure on public programs to seek improved pricing mechanisms for antihemophilic factor and other highly efficacious, high-cost medications,” the authors write.

“Our study underscores the potential effect of new, expensive but efficacious pharmaceuticals on public insurance programs for children with chronic illness. These findings may inform efforts to enhance value in these programs, particularly as new insurance frameworks, such as accountable care organizations, are considered.”

(doi:10.1001/jama.2015.7169; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The work was funded by a grant from the California HealthCare Foundation. The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, JULY 21, 2015

Media Advisory: To contact Shinji Nakahara, M.D., Ph.D., email snakahara-tky@umin.net. To contact Carolina Malta Hansen, M.D., call Samiha Khanna at 919-419-5069 or email samiha.khanna@duke.edu. To contact editorial co-author Graham Nichol, M.D., M.P.H., F.R.C.P., call Susan Gregg at 206-616-6730 or email sghanson@uw.edu.

To place an electronic embedded link to these studies and editorial in your story This link to the 1^st study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.8068 This link to the 2nd study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.7938 This will be the link to the editorial: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.7519

Two studies in the July 21 issue of JAMA find that use of interventions such as cardiopulmonary resuscitation and automated external defibrillators by bystanders and first responders have increased and were associated with improved survival and neurological outcomes for persons who experienced an out-of-hospital cardiac arrest.

Out-of-hospital cardiac arrest (OHCA) is an increasing health concern worldwide, with poor prognoses. Shinji Nakahara, M.D., Ph.D., of the Kanagawa University of Human Services, Yokosuka, Japan, and colleagues examined the associations between bystander interventions and changes in neurologically intact survival among patients with OHCA in Japan. The researchers used data from Japan’s nationwide OHCA registry, which started in January 2005. The registry includes all patients with OHCA transported to the hospital by emergency medical services (EMS) and recorded patients’ characteristics, prehospital interventions (including defibrillation using public-access automated external defibrillators [AEDs] and chest compression) and outcomes.

The study included 167,912 patients with bystander-witnessed OHCA between January 2005 and December 2012. The researchers found that during this time period, the number of these events increased and the rate of bystander chest compression, bystander-only defibrillation, and bystander defibrillation combined with EMS defibrillation also increased. In addition, likelihood of neurologically intact survival improved (age-adjusted proportion, 3.3 percent to 8.2 percent), but remained quite low. The increase in neurologically intact survival was associated with bystander defibrillation and chest compressions.

The authors write that further increases in use of chest compression by bystanders should be promoted. “In Japan it is used in just 50 percent of patients and is increasing slowly. Simplifying the basic life support procedure by omitting mouth-to-mouth breathing may have reduced hesitancy and increased its use. Facilitating chest compression has an economic advantage over deployment of expensive public-access AEDs. Fire departments provide training to more than 1,400,000 citizens every year to increase the prevalence of skills in basic resuscitation procedures, including chest compression and AED use. This effort should be further strengthened.”

(doi:10.1001/jama.2015.8068; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Carolina Malta Hansen, M.D., of the Duke Clinical Research Institute, Durham, N.C., and colleagues examined the outcomes and changes in bystander and first-responder resuscitation efforts for cardiac arrest patients before arrival of the EMS following statewide initiatives to improve these efforts in North Carolina.

Out-of-hospital cardiac arrest is a major public health issue, associated with low survival and accounting for approximately 200,000 deaths per year in the United States. Early cardiopulmonary resuscitation (CPR) and defibrillation can improve outcomes if more widely adopted, according to background information in the article.

This study included 4,961 patients with out-of-hospital cardiac arrest for whom resuscitation was attempted and who were identified through the Cardiac Arrest Registry to Enhance Survival (2010-2013). First responders included police officers, firefighters, rescue squad, or life-saving crew trained to perform basic life support until arrival of the EMS. Statewide initiatives to improve bystander and first-responder interventions included training members of the general population in CPR and in use of AEDs, training first responders in team-based CPR including AED use and high-performance CPR, and training dispatch centers in recognition of cardiac arrest.

The combination of bystander CPR and first-responder defibrillation increased from 14 percent (51 of 362) in 2010 to 23 percent (104 of 451) in 2013. Survival with favorable neurological outcome increased from 7 percent in 2010 to 10 percent in 2013 and was associated with bystander-initiated CPR. Bystander and first-responder interventions were associated with higher survival to hospital discharge. Survival following EMS-initiated CPR and defibrillation was 15 percent compared with 34 percent following bystander-initiated CPR and defibrillation; 24 percent following bystander CPR and first-responder defibrillation; and 25 percent following first-responder CPR and defibrillation

“Our study presents novel findings indicating that improvements in bystander and first-responder CPR and defibrillation are both associated with increased survival,” the authors write. “Our findings suggest the possibility of improving outcomes by strengthening first-responder programs, in addition to increasing the number of bystanders who could then provide CPR, including those assisted by emergency dispatchers, and by improving EMS systems. This is particularly important for cardiac arrests that occur in residential areas and in areas with a long EMS response time, where public access defibrillation programs are unlikely to be implemented.”

(doi:10.1001/jama.2015.7938; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was supported by the HeartRescue Project, which is funded by the Medtronic Foundation. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Editorial: Bystander Interventions Can Improve Outcomes From Out-of-Hospital Cardiac Arrest

“Despite increased knowledge and use of bystander CPR as well as improved survival over time, ongoing efforts are needed to improve outcomes after OHCA,” write Graham Nichol, M.D., M.P.H., F.R.C.P., and Francis Kim, M.D., of the University of Washington, Seattle, in an accompanying editorial.

“Mortality after resuscitation from cardiac arrest continues to be high in many communities. Further improvements in outcomes will require additional coordinated efforts to improve resuscitation care. The Institute of Medicine has released a report that describes multiple steps to improve outcomes after cardiac arrest. Key recommendations of this report include simple, sustainable high-quality efforts to measure and improve the process and outcome of care, as well as increased training of EMS personnel and leadership and funding for resuscitation research. The current studies by Malta Hansen et al and by Nakahara et al demonstrate the potential benefit these changes can have on resuscitation outcomes. Lay persons can improve outcomes after cardiac arrest in their community by participating in their system of care as well as supporting increased measurement and resuscitation research.”

(doi:10.1001/jama.2015.7519; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, JULY 21, 2015

Media Advisory: To contact Assiamira Ferrara, M.D., Ph.D., call Janet Byron at 510-891-3115 or email Janet.L.Byron@kp.org. To contact editorial co-author Joshua M. Sharfstein, M.D., call Barbara Benham at 410-614-6029 or email bbenham1@jhu.edu. To contact editorial co-author Phil B. Fontanarosa, M.D., M.B.A., call Jim Michalski at 312-464-5785 or email Jim.Michalski@jamanetwork.org.

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Although some previous studies have suggested an increased risk of bladder cancer with use of the diabetes drug pioglitazone, analyses that included nearly 200,000 patients found no statistically significant increased risk, however a small increased risk could not be excluded, according to a study in the July 21 issue of JAMA. Additional analyses with another large group found that use of pioglitazone was associated with an increase in the risk of prostate and pancreatic cancer, although further investigation is needed to assess whether the associations are causal or due to other factors.

Assiamira Ferrara, M.D., Ph.D., of Kaiser Permanente Northern California, Oakland, and colleagues studied with several groups of persons with diabetes: a bladder cancer cohort that followed 193,099 persons (40 years or older in 1997-2002) until December 2012; 464 case patients and 464 matched controls were surveyed about additional confounders (factors that can influence outcomes that may improperly skew the results); and a cohort analysis of 10 additional cancers included 236,507 persons (40 years or older in 1997-2005) and followed until June 2012. The additional cancers were prostate, female breast, lung/bronchus, endometrial, colon, non-Hodgkin lymphoma, pancreas, kidney/renal pelvis, rectum, and melanoma. All cohorts were from Kaiser Permanente Northern California.

Among the persons in the bladder cancer cohort, 34,181 (18 percent) received pioglitazone (median duration, 2.8 years) and 1,261 had incident bladder cancer. Ever use of pioglitazone was not associated with bladder cancer risk. Results were similar in case-control analyses (pioglitazone use: 19.6 percent among case patients and 17.5 percent among controls).

In adjusted analyses, there was no association with 8 of the 10 additional cancers; ever use of pioglitazone was associated with increased risk of prostate cancer and pancreatic cancer. No clear patterns of risk for any cancer were observed for time since initiation, duration, or dose.

“These studies were conducted to address safety concerns related to the risk of cancer after treatment with pioglitazone,” the authors write.

“There was no statistically significant increased risk of bladder cancer associated with pioglitazone use. However, a small increased risk, as previously observed, could not be excluded. The increased prostate and pancreatic cancer risks associated with ever use of pioglitazone merit further investigation to assess whether the observed associations are causal or due to chance, residual confounding, or reverse causality.”

(doi:10.1001/jama.2015.7996; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The study was funded by a grant from Takeda Development Center Americas Inc. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Editorial: The Safety of Prescription Drugs

Joshua M. Sharfstein, M.D., of the Johns Hopkins Bloomberg School of Public Health, Baltimore, and Aaron S. Kesselheim, M.D., J.D., M.P.H., of Brigham and Women’s Hospital, Boston, comment on the findings of this study in an accompanying editorial.

“That these data from the report by Lewis et al shed new light on the safety of pioglitazone reflects the dynamic nature of many drug safety questions. As in this case, caution and further review are the appropriate responses to many safety signals. But when emerging available data—clinical, laboratory, observational, and even population-based studies— create a compelling picture of risk in excess of potential benefit to patients, the FDA should act to protect the public.”

(doi:10.1001/jama.2015.7151; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including financial disclosures, funding and support, etc.

Editorial: Evaluating Research on the Safety of Medical Therapies

In an accompanying editorial, Phil B. Fontanarosa, M.D., M.B.A., Executive Deputy Editor, JAMA, Chicago, and colleagues discuss the responsibility of medical journals to the health of the public in reviewing studies evaluating the potential relationship between drugs, devices, or vaccines and adverse outcomes.

“The findings of the study by Lewis et al demonstrating no statistically significant association between the use of pioglitazone and the risk of bladder cancer are important because of the prevalence of type 2 diabetes, fairly widespread use of pioglitazone, and safety concerns about this drug.”

“Even though no observational study examining the relationship between an exposure and an outcome can definitively establish ‘positive’ cause-and-effect results, and no observational study can definitively prove ‘negative’ results, each study adds to the totality of evidence regarding the safety of drugs, devices, and vaccines. By publishing the results of these studies, JAMA will continue to provide information physicians can use in discussions with patients and regulatory bodies can use in policy decisions about the benefits and risks of various therapies.”

(doi:10.1001/jama.2015.8232; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, JULY 21, 2015

Media Advisory: To contact Lisa A. Jackson, M.D., M.P.H., call Joan DeClaire at 206-287-2653 or email declaire.j@ghc.org.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.7916

In a phase 2 trial that included nearly 1,000 adults, the AS03 and MF59 adjuvants (a component that improves immune response of inactivated influenza vaccines) increased the immune responses to two doses of an inactivated H7N9 influenza vaccine, with AS03-adjuvanted formulations inducing the highest amount of antibody response, according to a study in the July 21 issue of JAMA.

In March 2013 the first human infections with the avian influenza A(H7N9) virus were reported in China, and since that time hundreds of cases have been documented. While most infections are believed to result from exposure to infected poultry, the potential for viral adaptation that would facilitate person-to-person transmission is a major concern. Previous experience with an inactivated H7N7 influenza vaccine indicated that hemagglutinin (a substance on the outer coat of the influenza virus) H7 is poorly immunogenic, necessitating evaluation of adjuvanted H7N9 vaccines, according to background information in the article.

Lisa A. Jackson, M.D., M.P.H., of Group Health Research Institute, Seattle, and colleagues randomly assigned 980 adults (19 through 64 years or age) to receive the H7N9 vaccine on days 0 and 21 at doses of 3.75 µg, 7.5 µg, 15 µg, and 45 µg of hemagglutinin with or without AS03 or MF59 adjuvant. The study was conducted at 5 U.S. sites from September 2013 through November 2013; safety follow-up was completed in January 2015.

Two doses of vaccine were required to induce detectable antibody titers in most participants. After 2 doses of an H7N9 formulation containing 15 µg of hemagglutinin given without adjuvant, with AS03 adjuvant, or with MF59 adjuvant, the proportion achieving an hemagglutination inhibition antibody (HIA) titer of 40 or higher was 2 percent without adjuvant (n = 94), 84 percent with AS03 adjuvant (n = 96), and 57 percent with MF59 adjuvant (n = 92).

The two schedules alternating AS03-and MF59-adjuvanted formulations led to lower geometric mean (average) titers (GMTs) than the group induced by two AS03-adjuvanted formulations but higher GMTs than two doses of MF59-adjuvanted formulation. Older age and prior administration of seasonal influenza vaccine were independently associated with a decreased antibody response.

“These results imply that, of the options currently available utilizing adjuvants included in the national stockpile, based on the immune response data, AS03 should be considered a first-line adjuvant for strategies incorporating an inactivated H7N9 vaccine in adults,” the authors write.

“This study of 2 adjuvants used in influenza vaccine formulations with adjuvant mixed on site provides immunogenicity information that may be informative to influenza pandemic preparedness programs.”

(doi:10.1001/jama.2015.7916; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, JULY 21, 2015

Media Advisory: To contact Anton Pottegard, M.Sc.Pharm., Ph.D., email apottegaard@health.sdu.dk.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.6669

Researchers have found an association between treatment with the antibiotic dicloxacillin and a decrease in international normalized ratio (INR; a measure of blood coagulation) levels among patients taking the vitamin K antagonists warfarin or phenprocoumon, according to a study in the July 21 issue of JAMA.

A challenge in the use of vitamin K antagonists (VKAs) is the potential for drug-drug interactions, resulting in insufficient or excessive anticoagulation. Solid data are lacking for most alleged interactions. In case reports, the commonly used antibiotic dicloxacillin has been reported to lower the anticoagulant effect of warfarin, the most used VKA, according the background information in the article.

Anton Pottegard, M.Sc.Pharm., Ph.D., of the University of Southern Denmark, Odense, and colleagues identified patients currently taking warfarin via the anticoagulant database Thrombobase, a clinical database of all VKA-treated patients (n = 7,400) followed up by 3 outpatient clinics and 50 general practitioners in Funen, Denmark. The researchers included all patients who filled a prescription for dicloxacillin while receiving warfarin therapy between March 1998 and November 2012. INR results were grouped by the week relative to dicloxacillin exposure. The last INR measurement before dicloxacillin exposure was compared with the first measurement within weeks 2 to 4 after dicloxacillin exposure. The authors also assessed the use of dicloxacillin among patients taking another VKA, phenprocoumon.

Of 519 patients taking warfarin and initiating treatment with dicloxacillin, 236 met inclusion criteria. The average INR level prior to dicloxacillin exposure was 2.6 compared with 2, 2 to 4 weeks after dicloxacillin exposure, an average decrease of 0.6. In total, 61 percent (n = 144) experienced sub-therapeutic INR levels (<2.0) within 2 to 4 weeks after dicloxacillin treatment.

Among patients taking phenprocoumon (n = 64), average INR levels were 2.6 before exposure to dicloxacillin compared with 2.3 after exposure, an average decrease of 0.3. The proportion with sub-therapeutic INR levels after dicloxacillin exposure was 41 percent (n = 26).

“Physicians should be aware that dicloxacillin treatment may cause a significant decrease in INR levels among patients taking VKAs,” the authors write.

(doi:10.1001/jama.2015.6669; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, JULY 14, 2015

Media Advisory: To contact Udo Hoffmann, M.D., M.P.H., call McKenzie Ridings at 617-726-0274 or email mridings@partners.org. To contact Ankur Pandya, Ph.D., call Marge Dwyer at 617-432-8416 or email mhdwyer@hsph.harvard.edu. To contact editorial co-author Philip Greenland, M.D., call Marla Paul at 312-503-8928 or email marla-paul@northwestern.edu.

To place an electronic embedded link to these studies and editorial in your story This link to the 1^st study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.7515 This link to the 2^nd study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.6822 This will be the link to the editorial: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.7434

An examination of the 2013 guidelines for determining statin eligibility, compared to guidelines from 2004, indicates that they are associated with greater accuracy and efficiency in identifying increased risk of cardiovascular disease (CVD) events and presence of subclinical coronary artery disease, particularly in individuals at intermediate risk, according to a study in the July 14 issue of JAMA.

The 2013 American College of Cardiology/American Heart Association (ACC/AHA) guidelines for the management of blood cholesterol represent a shift in the treatment approach for the primary prevention of CVD, from focusing on the treatment of traditional risk factors, including the management of low-density lipoprotein cholesterol levels, to absolute cardiovascular risk as estimated by the 10-year atherosclerotic CVD (ASCVD) score for statin treatment. It has been unclear whether this approach improves identification of adults at higher risk of cardiovascular events, according to background information in the article.

Udo Hoffmann, M.D., M.P.H., of Massachusetts General Hospital and Harvard Medical School, Boston, and colleagues conducted a study determine whether the ACC/AHA guidelines improve identification of individuals who develop incident CVD and/or have coronary artery calcification (CAC) compared with the National Cholesterol Education Program’s Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP III) guidelines. The study included participants from the offspring and third-generation cohorts of the Framingham Heart Study. Participants underwent multi-detector computed tomography for CAC between 2002 and 2005 and were followed up for a median of 9 years for new CVD.

The study population consisted of 2,435 participants not taking lipid-lowering therapy. The average age was 51 years; 56 percent were women. There were a total of 74 (3 percent) incident CVD events (40 nonfatal heart attacks, 31 nonfatal strokes, and 3 with fatal coronary heart disease [CHD]) and 43 (2 percent) incident CHD events (40 non­fatal heart attacks and 3 with fatal CHD).

The researchers found that overall, more participants were eligible for statin treatment when applying the 2013 ACC/AHA guidelines compared with the 2004 ATP III guidelines (39 percent vs 14 percent). Among those eligible for statin treatment by the ATP III guidelines, 7 percent developed incident CVD compared with 2 percent among noneligible participants. Applying the ACC/AHA guidelines, among those eligible for statin treatment, 6 percent developed incident CVD compared with only 1 percent among those not eligible. The hazard ratio (risk) of having incident CVD among statin-eligible vs noneligible participants was also higher when applying the ACC/AHA guidelines’ statin eligibility criteria compared with the ATP III guidelines. “This finding is consistent across subgroups and particularly important in participants at intermediate CVD risk on the Framingham Risk Scores, the most challenging group in clinical practice for whom to decide to initiate statin therapy.”

Participants with CAC were more likely to be statin eligible by ACC/AHA than by ATP III.

The authors write that extrapolating their findings to the approximately 10 million U.S. adults who are newly eligible for statins, an estimated 41,000 to 63,000 incident CVD events would be prevented over a 10-year period by adopting the ACC/AHA guidelines. They note that the absolute cardiovascular event risk of statin-noneligible adults is not much lower with the ACC/AHA guidelines (1 percent) compared with the ATP III guidelines (2.4 percent), and the larger benefit may be that the ACC/AHA guidelines identify many more statin-eligible participants with a similarly high event rate as the ATP III guidelines (6.3 percent vs 6.9 percent).

The researchers add that a risk-benefit analysis considering costs and potential adverse effects of statins, especially in patients with prediabetes and in lower-risk patients, is needed to provide a complete assessment of the effects of the change in statin eligibility guidelines on the health care system.

(doi:10.1001/jama.2015.7515; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This work was supported by the National Heart, Lung, and Blood Institute’s Framingham Heart Study. Dr. Pursnani was supported by a National Institutes of Health grant. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

A microsimulation model-based analyses suggests that the health benefits associated with the 10-year atherosclerotic cardiovascular disease risk threshold of 7.5 percent or higher used in the 2013 ACC-AHA cholesterol guidelines are worth the additional costs required to achieve these health gains, and that a more lenient threshold might also be cost-effective, according to a study in the July 14 issue of JAMA.

In November 2013 the American College of Cardiology and the American Heart Association (ACC/AHA) released new recommendations to guide statin treatment initiation for the primary prevention of cardiovascular disease. These guidelines established 4 categories for statin treatment eligibility for adults 40 to 75 years of age, including 10-year atherosclerotic cardiovascular disease (ASCVD) risk of 7.5 percent or higher. It has been estimated that based on the new ASCVD risk threshold that 8.2 million additional adults in the U.S. would be recommended for statin treatment compared with previous recommendations. This expansion of statin treatment eligibility has been controversial, with some critics arguing that the guidelines substantially overestimate risk, and when taken in conjunction with more lenient treatment thresholds, millions of adults in the U.S. would be exposed to unnecessary statin treatment costs and risks, according to background information in the article.

Ankur Pandya, Ph.D., of the Harvard T.H. Chan School of Public Health, Boston, and colleagues performed a cost-effectiveness analysis of the ACC/AHA cholesterol treatment guidelines. With use of a microsimulation model, hypothetical individuals from a representative U.S. population 40 to 75 years of age received statin treatment, experienced ASCVD events, and died from ASCVD-related or non-ASCVD-related causes based on ASCVD natural history and statin treatment parameters. Data sources for model parameters included National Health and Nutrition Examination Surveys, large clinical trials and meta-analyses for statin benefits and treatment, and other published sources.

The researchers found that the current ASCVD threshold of 7.5 percent or higher, which was estimated to be associated with 48 percent of adults treated with statins, had an incremental cost-effectiveness ratio (ICER) of $37,000/quality-adjusted life-year (QALY) compared with a 10 percent or higher threshold. More lenient ASCVD thresholds of 4.0 percent or higher (61 percent of adults treated) and 3.0 percent or higher (67 percent of adults treated) had ICERs of $81,000/QALY and $140,000/QALY, respectively.

Shifting from the 7.5 percent or higher threshold to 3.0 percent or higher to 4.0 percent or higher was associated with an estimated additional 125,000 to 160,000 CVD events averted.

The optimal ASCVD threshold was sensitive to patient preferences for taking a pill daily, changes to statin price, and the risk of statin-induced diabetes.

“The decision to initiate statin treatment for adults without CVD should ultimately be informed by both evidence-based policies and patient preferences,” the authors write.

(doi:10.1001/jama.2015.6822; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This work is supported by a grant to the Harvard School of Public Health from the National Heart, Lung, and Blood Institute (Dr. Gaziano). Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Please Note: A podcast interview on this study is available at https://media.jamanetwork.com.

Editorial: Cholesterol Lowering in 2015

“Based on available evidence, including the 2 reports in this issue of JAMA, answers to the questions of in whom and how regarding cholesterol lowering are now more clear than they were just 18 months ago,” write Philip Greenland, M.D., of the Northwestern University Feinberg School of Medicine, Chicago, and Senior Editor, JAMA, and Michael S. Lauer, M.D., of the National Heart, Lung, and Blood Institute, Bethesda, Md., in an accompanying editorial.

“Available evidence indicates that statins are both effective and cost-effective for primary prevention even among low-risk individuals. Although lifestyle interventions must be employed across all segments of the population, for many people a statin drug will also be required to minimize risk. Where to set the treatment threshold and how to determine the individual’s level of risk are also becoming progressively clarified.”

“There is no longer any question as to whether to offer treatment with statins for patients for primary prevention, and there should now be fewer questions about how to treat and in whom. Rather, the next phase of research should be directed at better ways of applying lifestyle and drug treatments to the millions, and possibly billions, worldwide who could potentially benefit from a cost-effective approach to primary prevention of ASCVD.”

(doi:10.1001/jama.2015.7434; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including financial disclosures, funding and support, etc.

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